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1
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Yu SP, Choi E, Jiang MQ, Wei L. Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease. Neural Regen Res 2025; 20:1981-1988. [PMID: 39101641 PMCID: PMC11691467 DOI: 10.4103/nrr.nrr-d-24-00398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/13/2024] [Accepted: 07/04/2024] [Indexed: 08/06/2024] Open
Abstract
Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca 2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca 2+ mainly via N-methyl-D-aspartate receptors, particularly of those at the extrasynaptic site. This Ca 2+ -evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca 2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic, but gradually set off deteriorating Ca 2+ -dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca 2+ hypothesis of Alzheimer's disease and recent advances, this Ca 2+ -activated "silent" degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer's disease, therefore, share an N-methyl-D-aspartate receptor- and Ca 2+ -mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca 2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.
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Affiliation(s)
- Shan Ping Yu
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
- Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA
| | - Emily Choi
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Michael Q. Jiang
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
- Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA
| | - Ling Wei
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
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2
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Zhang X, Cai W, Wang C, Tian J. N-methyl-d-aspartate receptors (NMDARs): a glutamate-activated cation channel with biased signaling and therapeutic potential in brain disorders. Pharmacol Ther 2025:108888. [PMID: 40412765 DOI: 10.1016/j.pharmthera.2025.108888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 04/21/2025] [Accepted: 05/15/2025] [Indexed: 05/27/2025]
Abstract
N-methyl-d-aspartate receptors (NMDARs) are a type of calcium-permeable ion channel receptors that are extensively distributed throughout the body, composed of various subunits. The presence of diverse ligands and subcellular localizations of the receptors confer biased signaling and distinct functional roles. Activation of the NMDARs induces calcium influx, which plays a pivotal role in neurotransmitter release, synaptic plasticity, and intracellular signaling. Differential localization of NMDARs at synaptic and extrasynaptic sites results in divergent physiological effects; excessive or insufficient activation of NMDARs disrupts calcium homeostasis, leading to neuronal damage and subsequent neurological dysfunction as well as related diseases. Therefore, it is crucial to develop drugs targeting NMDAR with high efficacy with low toxicity for treating disorders associated with NMDARs abnormalities. In this review, we summarize both fundamental and clinical studies on NMDARs while discussing potential therapeutic targets aimed at modulating ion channel activity through regulating mechanisms, subunit rearrangement, membrane expression, and the specific targeting of synaptic versus extrasynaptic NMDARs. Our goal is to provide new insights for innovative drug development.
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Affiliation(s)
- Xuan Zhang
- Institute of Brain Disease and Data Analysis, College of Life Sciences and Oceanography, Shenzhen University, 518060, Guangdong, PR China
| | - Wensheng Cai
- Institute of Brain Disease and Data Analysis, College of Life Sciences and Oceanography, Shenzhen University, 518060, Guangdong, PR China
| | - Chao Wang
- Chemical Analysis & Physical Testing Institute, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, Guang Dong, PR China
| | - Jing Tian
- Institute of Brain Disease and Data Analysis, College of Life Sciences and Oceanography, Shenzhen University, 518060, Guangdong, PR China.
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Hwang EK, Wunsch AM, Wolf ME. Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving. Mol Psychiatry 2025:10.1038/s41380-025-03026-9. [PMID: 40316677 DOI: 10.1038/s41380-025-03026-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 03/06/2025] [Accepted: 04/08/2025] [Indexed: 05/04/2025]
Abstract
Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca2+-permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs. This is observed only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, we observe CP-AMPAR upregulation in D1 MSN (but not D2 MSN) and the effect of exogenous RA application is occluded in these D1 MSN. Instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of 'incubated rats' normalizes elevated cue-induced cocaine seeking back to non-incubated levels. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.
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Affiliation(s)
- Eun-Kyung Hwang
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
| | - Amanda M Wunsch
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
- National Center for Wellness and Recovery, Oklahoma State University Center for Health Sciences, Tulsa, OK, 74107, USA
| | - Marina E Wolf
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA.
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Camp CR, Banke TG, Xing H, Yu K, Perszyk RE, Epplin MP, Akins NS, Zhang J, Benke TA, Yuan H, Liotta DC, Traynelis SF. Selective Enhancement of the Interneuron Network and Gamma-Band Power via GluN2C/GluN2D NMDA Receptor Potentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.05.622179. [PMID: 39574703 PMCID: PMC11580944 DOI: 10.1101/2024.11.05.622179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
N-methyl-D-aspartate receptors (NMDARs) comprise a family of ligand-gated ionotropic glutamate receptors that mediate a slow, calcium-permeable component to excitatory neurotransmission. The GluN2D subunit is enriched in GABAergic inhibitory interneurons in cortical tissue. Diminished levels of GABAergic inhibition contribute to multiple neuropsychiatric conditions, suggesting that enhancing inhibition may have therapeutic utility, thus making GluN2D modulation an attractive drug target. Here, we describe the actions of a GluN2C/GluN2D-selective positive allosteric modulator (PAM), (+)-EU1180-453, which has improved drug-like properties such as increased aqueous solubility compared to the first-in-class GluN2C/GluN2D-selective prototypical PAM (+)-CIQ. (+)-EU1180-453 doubles the NMDAR response at lower concentrations (< 10 μM) compared to (+)-CIQ, and produces a greater degree of maximal potentiation at 30 μM. Using in vitro electrophysiological recordings, we show that (+)-EU1180-453 potentiates triheteromeric NMDARs containing at least one GluN2C or GluN2D subunit, and is active at both exon5-lacking and exon5-containing GluN1 splice variants. (+)-EU1180-453 increases glutamate efficacy for GluN2C/GluN2D-containing NMDARs by both prolonging the deactivation time and potentiating the peak response amplitude. We show that (+)-EU1180-453 selectively increases synaptic NMDAR-mediated charge transfer onto P11-15 CA1 stratum radiatum hippocampal interneurons, but is without effect on CA1 pyramidal cells. This increased charge transfer enhances inhibitory output from GABAergic interneurons onto CA1 pyramidal cells in a GluN2D-dependent manner. (+)-EU1180-453 also shifts excitatory-to-inhibitory coupling towards increased inhibition and produces enhanced gamma band power from carbachol-induced field potential oscillations in hippocampal slices. Thus, (+)-EU1180-453 can enhance overall circuit inhibition, which could prove therapeutically useful for the treatment of anxiety, depression, schizophrenia, and other neuropsychiatric disorders. Significance Statement Interneuron dysfunction and diminished GABAergic inhibition in neocortical and hippocampal circuits remains a prominent molecular hypothesis for neuropsychiatric diseases including anxiety, depression, and schizophrenia. Pharmacological agents that boost GABA receptor function have shown utility in various forms of depression and treating symptoms of schizophrenia. Cortical GABAergic interneurons, unlike their excitatory pyramidal cell counterparts, are enriched for the GluN2D subunit of the NMDA receptor. Thus, GluN2D subunit-selective modulation could be a useful therapeutic tool to enhance local inhibition, improving the prognosis for neuropsychiatric diseases for which interneuron dysfunction is prominent and causal to circuit aberration.
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Affiliation(s)
- Chad R. Camp
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tue G. Banke
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Hao Xing
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Kuai Yu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Riley E. Perszyk
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Matthew P. Epplin
- Department of Chemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Nicholas S. Akins
- Department of Chemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jing Zhang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Tim A. Benke
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Hongjie Yuan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Dennis C. Liotta
- Department of Chemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Stephen F. Traynelis
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
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Wunsch AM, Hwang EK, Funke JR, Baker R, Moutier A, Milovanovic M, Green TA, Wolf ME. Retinoic acid-mediated homeostatic plasticity in the nucleus accumbens core contributes to incubation of cocaine craving. Psychopharmacology (Berl) 2024; 241:1983-2001. [PMID: 38935096 DOI: 10.1007/s00213-024-06612-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 05/10/2024] [Indexed: 06/28/2024]
Abstract
RATIONALE Incubation of cocaine craving refers to the progressive intensification of cue-induced craving during abstinence from cocaine self-administration. We showed previously that homomeric GluA1 Ca2+-permeable AMPARs (CP-AMPAR) accumulate in excitatory synapses of nucleus accumbens core (NAcc) medium spiny neurons (MSN) after ∼1 month of abstinence and thereafter their activation is required for expression of incubation. Therefore, it is important to understand mechanisms underlying CP-AMPAR plasticity. OBJECTIVES We hypothesize that CP-AMPAR upregulation represents a retinoic acid (RA)-dependent form of homeostatic plasticity, previously described in other brain regions, in which a reduction in neuronal activity disinhibits RA synthesis, leading to GluA1 translation and CP-AMPAR synaptic insertion. We tested this using viral vectors to bidirectionally manipulate RA signaling in NAcc during abstinence following extended-access cocaine self-administration. RESULTS We used shRNA targeted to the RA degradative enzyme Cyp26b1 to increase RA signaling. This treatment accelerated incubation; rats expressed incubation on abstinence day (AD) 15, when it is not yet detected in control rats. It also accelerated CP-AMPAR synaptic insertion measured with slice physiology. CP-AMPARs were detected in Cyp26b1 shRNA-expressing MSN, but not control MSN, on AD15-18. Next, we used shRNA targeted to the major RA synthetic enzyme Aldh1a1 to reduce RA signaling. In MSN expressing Aldh1a1 shRNA, synaptic CP-AMPARs were reduced in late withdrawal (AD42-60) compared to controls. However, we did not detect an effect of this manipulation on incubated cocaine seeking (AD40). CONCLUSIONS These findings support the hypothesis that increased RA signaling during abstinence contributes to CP-AMPAR accumulation and incubation of cocaine craving.
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Affiliation(s)
- Amanda M Wunsch
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Eun-Kyung Hwang
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
| | - Jonathan R Funke
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA, 02111, USA
| | - Raines Baker
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
- College of Education, Health, and Human Sciences, Florida State University, Tallahassee, FL, 32306, USA
| | - Alana Moutier
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
- Yecuris Corporation, Tualatin, OR, 97062, USA
| | - Mike Milovanovic
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Thomas A Green
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Marina E Wolf
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA.
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.
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Beaurain M, Salabert AS, Payoux P, Gras E, Talmont F. NMDA Receptors: Distribution, Role, and Insights into Neuropsychiatric Disorders. Pharmaceuticals (Basel) 2024; 17:1265. [PMID: 39458906 PMCID: PMC11509972 DOI: 10.3390/ph17101265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND N-methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family. These ligand-gated channels are entwined with numerous fundamental neurological functions within the central nervous system (CNS), and numerous neuropsychiatric disorders may arise from their malfunction. METHODS The purpose of the present review is to provide a detailed description of NMDARs by addressing their molecular structures, activation mechanisms, and physiological roles in the mammalian brain. In the second part, their role in various neuropsychiatric disorders including stroke, epilepsy, anti-NMDA encephalitis, Alzheimer's and Huntington's diseases, schizophrenia, depression, neuropathic pain, opioid-induced tolerance, and hyperalgesia will be covered. RESULTS Finally, through a careful exploration of the main non-competitive NMDARs antagonists (channel-blockers). CONCLUSION We discuss the strengths and limitations of the various molecular structures developed for diagnostic or therapeutic purposes.
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Affiliation(s)
- Marie Beaurain
- ToNIC, Toulouse NeuroImaging Center, INSERM, UPS, Université de Toulouse, 31024 Toulouse, France; (M.B.); (A.-S.S.); (P.P.)
| | - Anne-Sophie Salabert
- ToNIC, Toulouse NeuroImaging Center, INSERM, UPS, Université de Toulouse, 31024 Toulouse, France; (M.B.); (A.-S.S.); (P.P.)
| | - Pierre Payoux
- ToNIC, Toulouse NeuroImaging Center, INSERM, UPS, Université de Toulouse, 31024 Toulouse, France; (M.B.); (A.-S.S.); (P.P.)
| | - Emmanuel Gras
- Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA, UMR 5069), CNRS, UPS, Université de Toulouse, 118 Route de Narbonne, CEDEX 9, 31062 Toulouse, France;
| | - Franck Talmont
- Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS, UPS, Université de Toulouse, 31077 Toulouse, France
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Hwang EK, Wunsch AM, Wolf ME. Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.12.611703. [PMID: 39314388 PMCID: PMC11419102 DOI: 10.1101/2024.09.12.611703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca2+-permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs, and that this pathway is operative only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, this effect of RA is occluded; instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of 'incubated rats' normalizes the incubation-associated elevation of cue-induced cocaine seeking. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.
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Affiliation(s)
- Eun-Kyung Hwang
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, U.S.A. 97212
| | - Amanda M Wunsch
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, U.S.A. 97212
| | - Marina E Wolf
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, U.S.A. 97212
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Lu WH, Chang TT, Chang YM, Liu YH, Lin CH, Suen CS, Hwang MJ, Huang YS. CPEB2-activated axonal translation of VGLUT2 mRNA promotes glutamatergic transmission and presynaptic plasticity. J Biomed Sci 2024; 31:69. [PMID: 38992696 PMCID: PMC11241979 DOI: 10.1186/s12929-024-01061-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 07/02/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Local translation at synapses is important for rapidly remodeling the synaptic proteome to sustain long-term plasticity and memory. While the regulatory mechanisms underlying memory-associated local translation have been widely elucidated in the postsynaptic/dendritic region, there is no direct evidence for which RNA-binding protein (RBP) in axons controls target-specific mRNA translation to promote long-term potentiation (LTP) and memory. We previously reported that translation controlled by cytoplasmic polyadenylation element binding protein 2 (CPEB2) is important for postsynaptic plasticity and memory. Here, we investigated whether CPEB2 regulates axonal translation to support presynaptic plasticity. METHODS Behavioral and electrophysiological assessments were conducted in mice with pan neuron/glia- or glutamatergic neuron-specific knockout of CPEB2. Hippocampal Schaffer collateral (SC)-CA1 and temporoammonic (TA)-CA1 pathways were electro-recorded to monitor synaptic transmission and LTP evoked by 4 trains of high-frequency stimulation. RNA immunoprecipitation, coupled with bioinformatics analysis, were used to unveil CPEB2-binding axonal RNA candidates associated with learning, which were further validated by Western blotting and luciferase reporter assays. Adeno-associated viruses expressing Cre recombinase were stereotaxically delivered to the pre- or post-synaptic region of the TA circuit to ablate Cpeb2 for further electrophysiological investigation. Biochemically isolated synaptosomes and axotomized neurons cultured on a microfluidic platform were applied to measure axonal protein synthesis and FM4-64FX-loaded synaptic vesicles. RESULTS Electrophysiological analysis of hippocampal CA1 neurons detected abnormal excitability and vesicle release probability in CPEB2-depleted SC and TA afferents, so we cross-compared the CPEB2-immunoprecipitated transcriptome with a learning-induced axonal translatome in the adult cortex to identify axonal targets possibly regulated by CPEB2. We validated that Slc17a6, encoding vesicular glutamate transporter 2 (VGLUT2), is translationally upregulated by CPEB2. Conditional knockout of CPEB2 in VGLUT2-expressing glutamatergic neurons impaired consolidation of hippocampus-dependent memory in mice. Presynaptic-specific ablation of Cpeb2 in VGLUT2-dominated TA afferents was sufficient to attenuate protein synthesis-dependent LTP. Moreover, blocking activity-induced axonal Slc17a6 translation by CPEB2 deficiency or cycloheximide diminished the releasable pool of VGLUT2-containing synaptic vesicles. CONCLUSIONS We identified 272 CPEB2-binding transcripts with altered axonal translation post-learning and established a causal link between CPEB2-driven axonal synthesis of VGLUT2 and presynaptic translation-dependent LTP. These findings extend our understanding of memory-related translational control mechanisms in the presynaptic compartment.
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Affiliation(s)
- Wen-Hsin Lu
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan
| | - Tzu-Tung Chang
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan
| | - Yao-Ming Chang
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan
| | - Yi-Hsiang Liu
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan
| | - Chia-Hsuan Lin
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming Chao-Tung University and Academia Sinica, Taipei, 11529, Taiwan
| | - Ching-Shu Suen
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan
| | - Ming-Jing Hwang
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan
| | - Yi-Shuian Huang
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd., Taipei, 11529, Taiwan.
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming Chao-Tung University and Academia Sinica, Taipei, 11529, Taiwan.
- Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, 11529, Taiwan.
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Brunetti V, Soda T, Berra-Romani R, De Sarro G, Guerra G, Scarpellino G, Moccia F. Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age. Biomedicines 2024; 12:880. [PMID: 38672234 PMCID: PMC11048239 DOI: 10.3390/biomedicines12040880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/02/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs), which mediate rapid synaptic depolarization that can be associated with Ca2+ entry and activity-dependent change in the strength of synaptic transmission, as well as by metabotropic glutamate receptors (mGluRs), which mediate slower postsynaptic responses through the recruitment of second messenger systems. A wealth of evidence reported over the last three decades has shown that this dogmatic subdivision between iGluRs and mGluRs may not reflect the actual physiological signaling mode of the iGluRs, i.e., α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors (AMPAR), kainate receptors (KARs), and N-methyl-D-aspartate (NMDA) receptors (NMDARs). Herein, we review the evidence available supporting the notion that the canonical iGluRs can recruit flux-independent signaling pathways not only in neurons, but also in brain astrocytes and cerebrovascular endothelial cells. Understanding the signaling versatility of iGluRs can exert a profound impact on our understanding of glutamatergic synapses. Furthermore, it may shed light on novel neuroprotective strategies against brain disorders.
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Affiliation(s)
- Valentina Brunetti
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, 27110 Pavia, Italy; (V.B.); (G.S.)
| | - Teresa Soda
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (T.S.); (G.D.S.)
| | - Roberto Berra-Romani
- Department of Biomedicine, School of Medicine, Benemérita Universidad Autónoma de Puebla, Puebla 72410, Mexico;
| | - Giovambattista De Sarro
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (T.S.); (G.D.S.)
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, 88110 Catanzaro, Italy
| | - Germano Guerra
- Department of Medicine and Health Science “Vincenzo Tiberio”, School of Medicine and Surgery, University of Molise, 86100 Campobasso, Italy;
| | - Giorgia Scarpellino
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, 27110 Pavia, Italy; (V.B.); (G.S.)
| | - Francesco Moccia
- Department of Medicine and Health Science “Vincenzo Tiberio”, School of Medicine and Surgery, University of Molise, 86100 Campobasso, Italy;
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10
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Yu SP, Jiang MQ, Shim SS, Pourkhodadad S, Wei L. Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer's disease. Mol Neurodegener 2023; 18:43. [PMID: 37400870 DOI: 10.1186/s13024-023-00636-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 06/01/2023] [Indexed: 07/05/2023] Open
Abstract
Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca2+ influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca2+ overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca2+ dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca2+ influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a "gatekeeper" role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca2+-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca2+ homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.
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Affiliation(s)
- Shan P Yu
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Center for Visual & Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA, 30033, USA.
| | - Michael Q Jiang
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Center for Visual & Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA, 30033, USA
| | - Seong S Shim
- Center for Visual & Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA, 30033, USA
| | - Soheila Pourkhodadad
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Center for Visual & Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA, 30033, USA
| | - Ling Wei
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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11
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Zhang M, Kong X, Chen J, Liu W, Liu C, Dou X, Jiang L, Luo Y, Song M, Miao P, Tang Y, Xiu Y. Dysfunction of GluN3A subunit is involved in depression-like behaviors through synaptic deficits. J Affect Disord 2023; 332:72-82. [PMID: 36997126 DOI: 10.1016/j.jad.2023.03.076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/07/2023] [Accepted: 03/24/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of depression. However, as the unique inhibitory subunit of NMDARs, the role of GluN3A in depression is largely unclear. METHODS Firstly, expression of GluN3A was examined in a mouse model of depression induced by chronic restraint stress (CRS). Then, rescue experiment with rAAV-Grin3a injection into hippocampus of CRS mice was carried out. Lastly, GluN3A knockout (KO) mouse was generated via CRISPR/Cas9 technique, and the molecular mechanism underlying involvement of GluN3A in depression was initially explored using RNA-seq technique, RT-PCR and western blotting. RESULTS GluN3A expression in hippocampus was significantly decreased in CRS mice. Depression-like behaviors induced by CRS were ameliorated when the decrease of GluN3A expression in mice exposed to CRS was restored. GluN3A KO mice exhibited symptoms of anhedonia reported as reduced sucrose preference, and symptoms of despair assayed by a longer immobility time in FST. Transcriptome analysis revealed genetic ablation of GluN3A was associated with downregulation of genes implicated in synapse and axon development. Postsynaptic protein PSD95 was decreased in GluN3A KO mice. More importantly, reduction of PSD95 in CRS mice can be rescued by viral mediated Grin3a re-expression. LIMITATIONS The mechanism underlying GluN3A involvement in depression is not fully determined. CONCLUSIONS Our data suggested that GluN3A dysfunction is involved in depression, which might be mediated by synaptic deficits. These findings will facilitate the understanding of the role of GluN3A in depression, and they might provide a new strategy for the development of subunit-selective NMDAR antagonists as antidepressant drugs.
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Affiliation(s)
- Mengmeng Zhang
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Xiangru Kong
- Department of Pediatric Surgical Oncology, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China
| | - Jing Chen
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Wenqin Liu
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Can Liu
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Xiaoyun Dou
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Lin Jiang
- Lab Teaching Management Center, Chongqing Medical University, Chongqing 400016, PR China
| | - Yanmin Luo
- Department of Physiology, Chongqing Medical University, Chongqing 400016, PR China
| | - Mingrui Song
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Peng Miao
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Yong Tang
- Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, PR China.
| | - Yun Xiu
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China.
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12
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Funke JR, Hwang EK, Wunsch AM, Baker R, Engeln KA, Murray CH, Milovanovic M, Caccamise AJ, Wolf ME. Persistent Neuroadaptations in the Nucleus Accumbens Core Accompany Incubation of Methamphetamine Craving in Male and Female Rats. eNeuro 2023; 10:ENEURO.0480-22.2023. [PMID: 36792361 PMCID: PMC10016192 DOI: 10.1523/eneuro.0480-22.2023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 02/17/2023] Open
Abstract
Relapse is a major problem in treating methamphetamine use disorder. "Incubation of craving" during abstinence is a rat model for persistence of vulnerability to craving and relapse. While methamphetamine incubation has previously been demonstrated in male and female rats, it has not been demonstrated after withdrawal periods greater than 51 d and most mechanistic work used males. Here, we address both gaps. First, although methamphetamine intake was higher in males during self-administration training (6 h/d × 10 d), incubation was similar in males and females, with "incubated" craving persisting through withdrawal day (WD)100. Second, using whole-cell patch-clamp recordings in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core, we assessed synaptic levels of calcium-permeable AMPA receptors (CP-AMPARs), as their elevation is required for expression of incubation in males. In both sexes, compared with saline-self-administering controls, CP-AMPAR levels were significantly higher in methamphetamine rats across withdrawal, although this was less pronounced in WD100-135 rats than WD15-35 or WD40-75 methamphetamine rats. We also examined membrane properties and NMDA receptor (NMDAR) transmission. In saline controls, MSNs from males exhibited lower excitability than females. This difference was eliminated after incubation because of increased excitability of MSNs from males. NMDAR transmission did not differ between sexes and was not altered after incubation. In conclusion, incubation persists for longer than previously described and equally persistent CP-AMPAR plasticity in NAc core occurs in both sexes. Thus, abstinence-related synaptic plasticity in NAc is similar in males and females although other methamphetamine-related behaviors and neuroadaptations show differences.
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Affiliation(s)
- Jonathan R Funke
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97212
| | - Eun-Kyung Hwang
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97212
| | - Amanda M Wunsch
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97212
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
| | - Raines Baker
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97212
| | - Kimberley A Engeln
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97212
| | - Conor H Murray
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
| | - Mike Milovanovic
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
| | - Aaron J Caccamise
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
| | - Marina E Wolf
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97212
- Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
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13
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Soda T, Brunetti V, Berra-Romani R, Moccia F. The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives. Int J Mol Sci 2023; 24:ijms24043914. [PMID: 36835323 PMCID: PMC9965111 DOI: 10.3390/ijms24043914] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate, mediate the slow component of excitatory neurotransmission in the central nervous system (CNS), and induce long-term changes in synaptic plasticity. NMDARs are non-selective cation channels that allow the influx of extracellular Na+ and Ca2+ and control cellular activity via both membrane depolarization and an increase in intracellular Ca2+ concentration. The distribution, structure, and role of neuronal NMDARs have been extensively investigated and it is now known that they also regulate crucial functions in the non-neuronal cellular component of the CNS, i.e., astrocytes and cerebrovascular endothelial cells. In addition, NMDARs are expressed in multiple peripheral organs, including heart and systemic and pulmonary circulations. Herein, we survey the most recent information available regarding the distribution and function of NMDARs within the cardiovascular system. We describe the involvement of NMDARs in the modulation of heart rate and cardiac rhythm, in the regulation of arterial blood pressure, in the regulation of cerebral blood flow, and in the blood-brain barrier (BBB) permeability. In parallel, we describe how enhanced NMDAR activity could promote ventricular arrhythmias, heart failure, pulmonary artery hypertension (PAH), and BBB dysfunction. Targeting NMDARs could represent an unexpected pharmacological strategy to reduce the growing burden of several life-threatening cardiovascular disorders.
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Affiliation(s)
- Teresa Soda
- Department of Health Sciences, University of Magna Graecia, 88100 Catanzaro, Italy
| | - Valentina Brunetti
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy
| | - Roberto Berra-Romani
- Department of Biomedicine, School of Medicine, Benemérita Universidad Autónoma de Puebla, Puebla 72410, Mexico
| | - Francesco Moccia
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy
- Correspondence: ; Tel.: +39-0382-987613
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14
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Ramírez A, Monjaraz E, Manjarrez E, Moyaho A, Cebada J, Flores A. Pharmacological characterization and differential expression of NMDA receptor subunits in the chicken vestibular system during development. Synapse 2023; 77:e22252. [PMID: 36099479 DOI: 10.1002/syn.22252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/31/2022] [Accepted: 09/04/2022] [Indexed: 01/29/2023]
Abstract
Previous studies demonstrated that in vitro preparations of the isolated vestibular system of diverse animal species still exhibit stable resting electrical activity and mechanically evoked synaptic transmission between hair cells and primary afferent endings. However, there are no reports related to their neurodevelopment. Therefore, this research aimed to examine whether NMDA receptors mediate these electrical signals in an isolated preparation of the chicken vestibular system at three developmental stages, E15, E18, and E21. We found that the spontaneous and mechanically evoked discharges from primary afferents of the posterior semicircular canal were modulated by agonists NMDA and glycine, but not by the agonist d-serine applied near the synapses. Moreover, the individually applied by bath perfusion of three NMDA receptor antagonists (MK-801, ifenprodil, and 2-naphthoic acid) or high Mg2+ decreased the resting discharge rate, the NMDA response, and the discharge rate of mechanically evoked activity from these primary afferents. Furthermore, we found that the vestibular ganglion shows a stage-dependent increase in the expression of NMDA receptor subunits GluN1, GluN2 (A-C), and GluN3 (A-B), being greater at E21, except for GluN2D, which was inversely related to the developmental stage. However, in the crista ampullaris, the expression pattern remained constant throughout development. This could suggest the possible existence of presynaptic NMDA receptors. Our results highlight that although the NMDA receptors are functionally active at the early embryonic stages of the vestibular system, NMDA and glycine reach their mature functionality to increase NMDA responses close to hatching (E21).
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Affiliation(s)
- Ana Ramírez
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México.,Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, México
| | - Eduardo Monjaraz
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México
| | - Elías Manjarrez
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México
| | - Alejandro Moyaho
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México
| | - Jorge Cebada
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, México
| | - Amira Flores
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México
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15
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Niu M, Yang X, Li Y, Sun Y, Wang L, Ha J, Xie Y, Gao Z, Tian C, Wang L, Sun Y. Progresses in GluN2A-containing NMDA Receptors and their Selective Regulators. Cell Mol Neurobiol 2023; 43:139-153. [PMID: 34978648 PMCID: PMC11415211 DOI: 10.1007/s10571-021-01185-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 12/18/2021] [Indexed: 01/07/2023]
Abstract
NMDA receptors play an important physiological role in regulating synaptic plasticity, learning and memory. GluN2A subunits are the most abundant functional subunits of NMDA receptors expressed in mature brain, and their dysfunction is related to various neurological diseases. According to subunit composition, GluN2A-containing NMDA receptors can be divided into two types: diheteromeric and triheteromeric receptors. In this review, the expression, functional and pharmacological properties of different kinds of GluN2A-containing NMDA receptors as well as selective GluN2A regulators were described to further understand this type of NMDA receptors.
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Affiliation(s)
- Menghan Niu
- Department of Pharmacy, Hebei University of Science and Technology, Yuhua East Road 70, Shijiazhuang, 050018, Hebei, China
| | - Xin Yang
- Department of Pharmaceutical Engineering, Hebei Chemical & Pharmaceutical College, Fangxing Road 88, Shijiazhuang, 050026, Hebei, China
- Hebei Technological Innovation Center of Chiral Medicine, Shijiazhuang, China
| | - Yuanyuan Li
- Department of Pharmacy, Hebei University of Science and Technology, Yuhua East Road 70, Shijiazhuang, 050018, Hebei, China
| | - Yanping Sun
- Department of Pharmacy, Hebei University of Science and Technology, Yuhua East Road 70, Shijiazhuang, 050018, Hebei, China
- Hebei Research Center of Pharmaceutical and Chemical Engineering, Hebei University of Science and Technology, Shijiazhuang, China
- State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Shijiazhuang, China
| | - Long Wang
- Department of Family and Consumer Sciences, California State University, Long Beach, USA
| | - Jing Ha
- Department of Pharmacy, Hebei University of Science and Technology, Yuhua East Road 70, Shijiazhuang, 050018, Hebei, China
| | - Yinghua Xie
- Department of Pharmacy, Hebei University of Science and Technology, Yuhua East Road 70, Shijiazhuang, 050018, Hebei, China
| | - Zibin Gao
- Department of Pharmacy, Hebei University of Science and Technology, Yuhua East Road 70, Shijiazhuang, 050018, Hebei, China
- Hebei Research Center of Pharmaceutical and Chemical Engineering, Hebei University of Science and Technology, Shijiazhuang, China
- State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Shijiazhuang, China
| | - Changzheng Tian
- Department of Anesthesiology, The First Hospital of Hebei Medical University, Donggang Road 89, Shijiazhuang, 050000, Hebei, China.
| | - Le Wang
- Department of Pharmaceutical Engineering, Hebei Chemical & Pharmaceutical College, Fangxing Road 88, Shijiazhuang, 050026, Hebei, China.
- Hebei Technological Innovation Center of Chiral Medicine, Shijiazhuang, China.
| | - Yongjun Sun
- Department of Pharmacy, Hebei University of Science and Technology, Yuhua East Road 70, Shijiazhuang, 050018, Hebei, China.
- Hebei Research Center of Pharmaceutical and Chemical Engineering, Hebei University of Science and Technology, Shijiazhuang, China.
- State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Shijiazhuang, China.
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16
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Lee K, Mills Z, Cheung P, Cheyne JE, Montgomery JM. The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders. Pharmaceuticals (Basel) 2022; 16:ph16010001. [PMID: 36678498 PMCID: PMC9866730 DOI: 10.3390/ph16010001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
NMDA-type glutamate receptors are critical for synaptic plasticity in the central nervous system. Their unique properties and age-dependent arrangement of subunit types underpin their role as a coincidence detector of pre- and postsynaptic activity during brain development and maturation. NMDAR function is highly modulated by zinc, which is co-released with glutamate and concentrates in postsynaptic spines. Both NMDARs and zinc have been strongly linked to autism spectrum disorders (ASDs), suggesting that NMDARs are an important player in the beneficial effects observed with zinc in both animal models and children with ASDs. Significant evidence is emerging that these beneficial effects occur via zinc-dependent regulation of SHANK proteins, which form the backbone of the postsynaptic density. For example, dietary zinc supplementation enhances SHANK2 or SHANK3 synaptic recruitment and rescues NMDAR deficits and hypofunction in Shank3ex13-16-/- and Tbr1+/- ASD mice. Across multiple studies, synaptic changes occur in parallel with a reversal of ASD-associated behaviours, highlighting the zinc-dependent regulation of NMDARs and glutamatergic synapses as therapeutic targets for severe forms of ASDs, either pre- or postnatally. The data from rodent models set a strong foundation for future translational studies in human cells and people affected by ASDs.
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17
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Khantakova JN, Bondar NP, Sapronova AA, Reshetnikov VV. Delayed effects of neonatal immune activation on brain neurochemistry and hypothalamic-pituitary-adrenal axis functioning. Eur J Neurosci 2022; 56:5931-5951. [PMID: 36156830 DOI: 10.1111/ejn.15831] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/17/2022] [Accepted: 09/15/2022] [Indexed: 12/29/2022]
Abstract
During the postnatal period, the brain is highly sensitive to stress and inflammation, which are hazardous to normal growth and development. There is increasing evidence that inflammatory processes in the early postnatal period increase the risk of psychopathologies and cognitive impairment later in life. On the other hand, there are few studies on the ability of infectious agents to cause long-term neuroinflammation, leading to changes in the hypothalamic-pituitary-adrenal axis functioning and an imbalance in the neurotransmitter system. In this review, we examine short- and long-term effects of neonatal-induced inflammation in rodents on glutamatergic, GABAergic and monoaminergic systems and on hypothalamic-pituitary-adrenal axis activity.
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Affiliation(s)
- Julia N Khantakova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk, Russia.,Federal State Budgetary Scientific Institution 'Research Institute of Fundamental and Clinical Immunology' (RIFCI), Novosibirsk, Russia
| | - Natalia P Bondar
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk, Russia.,Novosibirsk State University, Novosibirsk, Russia
| | - Anna A Sapronova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk, Russia
| | - Vasiliy V Reshetnikov
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk, Russia.,Sirius University of Science and Technology, Sochi, Russia
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18
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Chen J, Zhang J, Yang DD, Li ZC, Zhao B, Chen Y, He Z. Clonidine ameliorates cerebral ischemia-reperfusion injury by up-regulating the GluN3 subunits of NMDA receptor. Metab Brain Dis 2022; 37:1829-1841. [PMID: 35727521 DOI: 10.1007/s11011-022-01028-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/04/2022] [Indexed: 10/18/2022]
Abstract
This study aimed to investigate the protective effects of the alpha-2 adrenergic receptor (α2-AR) agonist, clonidine, on the cerebral ischemia-reperfusion (I/R) injury and elaborate the underlying mechanisms. Cerebral I/R model was established by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 4 h in adult male SD rats. Saline, clonidine and yohimbine (an α2-AR antagonist) were intraperitoneally administered each day for one week before surgery. Neurological deficit was evaluated just before decapitation. TTC staining was applied for correlation of cerebral infarction volume. HE staining was performed to observe the neuron morphology. Immunohistochemical staining was performed to detect the localization and expression of GluN3 proteins. Western blot analysis also was used to detect the expression levels of GluN3 proteins. Our data showed that clonidine ameliorated neurological deficit and reduced the cerebral infarction volume of the rats with cerebral I/R. It is worth noting that treatment with clonidine up-regulated the protein expression of GluN3 in the rats with the cerebral I/R, especially in the cell membrane. Moreover, clonidine also up-regulated the transposition from cytoplasm to cell membrane of GluN3 after cerebral I/R. In addition, yohimbine abolished the neuroprotective effects of clonidine. The results indicated that clonidine played a protective role in cerebral I/R injury through regulation of the protein expression of GluN3 subunits of N-methyl-D-aspartate (NMDA) receptor.
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Affiliation(s)
- Jing Chen
- Third-Grade Pharmacological Laboratory On Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, People's Republic of China
- Medical College, China Three Gorges University, Yichang, 443002, People's Republic of China
| | - Juan Zhang
- The First People's Hospital of Yichang, Yichang, 443000, People's Republic of China
| | - Dan-Dan Yang
- The Second People's Hospital of China Three Gorges University, Yichang, 443000, People's Republic of China
| | - Zi-Cheng Li
- Third-Grade Pharmacological Laboratory On Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, People's Republic of China
- Medical College, China Three Gorges University, Yichang, 443002, People's Republic of China
| | - Bo Zhao
- Third-Grade Pharmacological Laboratory On Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, People's Republic of China
- Medical College, China Three Gorges University, Yichang, 443002, People's Republic of China
| | - Yue Chen
- Third-Grade Pharmacological Laboratory On Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, People's Republic of China
- Medical College, China Three Gorges University, Yichang, 443002, People's Republic of China
| | - Zhi He
- Third-Grade Pharmacological Laboratory On Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, People's Republic of China.
- Medical College, China Three Gorges University, Yichang, 443002, People's Republic of China.
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19
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Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models. Neuropharmacology 2022; 213:109079. [PMID: 35561792 DOI: 10.1016/j.neuropharm.2022.109079] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/11/2022] [Accepted: 05/05/2022] [Indexed: 12/11/2022]
Abstract
Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.
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Abhari AP, Etemadifar M, Yazdanpanah N, Rezaei N. N-Methyl-D-Aspartate (NMDA)-Type Glutamate Receptors and Demyelinating Disorders: A Neuroimmune Perspective. Mini Rev Med Chem 2022; 22:2624-2640. [PMID: 35507747 DOI: 10.2174/1389557522666220504135853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/21/2021] [Accepted: 02/02/2022] [Indexed: 11/22/2022]
Abstract
N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors, highly important in regulating substantial physiologic processes in the brain and the nervous system, and disturbance in their function could contribute to different pathologies. Overstimulation and hyperactivity of NMDARs, termed as glutamate toxicity, could promote cell death and apoptosis. Meanwhile, their blockade could lead to dysfunction of the brain and nervous system as well. A growing body of evidence has demonstrated the prominent role of NMDARs in demyelinating disorders and anti-NMDAR encephalitis. Herein, we provide an overview of the role of NMDARs' dysfunction in the physiopathology of demyelinating disorders such as multiple sclerosis and neuromyelitis optica spectrum disorders.
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Affiliation(s)
- Amir Parsa Abhari
- Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Isfahan, Iran.,School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masoud Etemadifar
- Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Niloufar Yazdanpanah
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children\'s Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children\'s Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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21
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Herold C, Ockermann PN, Amunts K. Behavioral Training Related Neurotransmitter Receptor Expression Dynamics in the Nidopallium Caudolaterale and the Hippocampal Formation of Pigeons. Front Physiol 2022; 13:883029. [PMID: 35600306 PMCID: PMC9114877 DOI: 10.3389/fphys.2022.883029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/14/2022] [Indexed: 11/13/2022] Open
Abstract
Learning and memory are linked to dynamic changes at the level of synapses in brain areas that are involved in cognitive tasks. For example, changes in neurotransmitter receptors are prerequisite for tuning signals along local circuits and long-range networks. However, it is still unclear how a series of learning events promotes plasticity within the system of neurotransmitter receptors and their subunits to shape information processing at the neuronal level. Therefore, we investigated the expression of different glutamatergic NMDA (GRIN) and AMPA (GRIA) receptor subunits, the GABAergic GABARG2 subunit, dopaminergic DRD1, serotonergic 5HTR1A and noradrenergic ADRA1A receptors in the pigeon's brain. We studied the nidopallium caudolaterale, the avian analogue of the prefrontal cortex, and the hippocampal formation, after training the birds in a rewarded stimulus-response association (SR) task and in a simultaneous-matching-to-sample (SMTS) task. The results show that receptor expression changed differentially after behavioral training compared to an untrained control group. In the nidopallium caudolaterale, GRIN2B, GRIA3, GRIA4, DRD1D, and ADRA1A receptor expression was altered after SR training and remained constantly decreased after the SMTS training protocol, while GRIA2 and DRD1A decreased only under the SR condition. In the hippocampal formation, GRIN2B decreased and GABARG2 receptor expression increased after SR training. After SMTS sessions, GRIN2B remained decreased, GABARG2 remained increased if compared to the control group. None of the investigated receptors differed directly between both conditions, although differentially altered. The changes in both regions mostly occur in favor of the stimulus response task. Thus, the present data provide evidence that neurotransmitter receptor expression dynamics play a role in the avian prefrontal cortex and the hippocampal formation for behavioral training and is uniquely, regionally and functionally associated to cognitive processes including learning and memory.
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Affiliation(s)
- Christina Herold
- C. & O. Vogt-Institute for Brain Research, Medical Faculty, University Hospital and Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Philipp N. Ockermann
- C. & O. Vogt-Institute for Brain Research, Medical Faculty, University Hospital and Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Katrin Amunts
- C. & O. Vogt-Institute for Brain Research, Medical Faculty, University Hospital and Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
- Institute of Neuroscience and Medicine INM-1, Research Center Jülich, Jülich, Germany
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22
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Tyler RE, Bluitt MN, Engers JL, Lindsley CW, Besheer J. The effects of predator odor (TMT) exposure and mGlu 3 NAM pretreatment on behavioral and NMDA receptor adaptations in the brain. Neuropharmacology 2022; 207:108943. [PMID: 35007623 PMCID: PMC8844221 DOI: 10.1016/j.neuropharm.2022.108943] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 12/09/2021] [Accepted: 01/04/2022] [Indexed: 12/13/2022]
Abstract
A stressor can trigger lasting adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that may activate the metabotropic glutamate receptor 3 (mGlu3) to produce stress adaptations. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after, rats underwent context re-exposure, elevated zero maze (ZM), and acoustic startle (ASR) behavioral tests, followed by RT-PCR gene expression in the insular cortex and bed nucleus of the stria terminalis (BNST) to evaluate lasting behavioral and molecular adaptations from the stressor. Rats displayed stress-reactive behaviors in response to TMT exposure that were not affected by VU6010572. Freezing and hyperactivity were observed during the context re-exposure, and mGlu3-NAM pretreatment during stressor prevented the context freezing response. TMT exposure did not affect ZM or ASR measures, but VU6010572 increased time spent in the open arms of the ZM and ASR habituation regardless of stressor treatment. In the insular cortex, TMT exposure increased expression of mGlu (Grm3, Grm5) and NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) receptor transcripts, and mGlu3-NAM pretreatment blocked GriN3B upregulation. In the BNST, TMT exposure increased expression of GriN2B and GriN3B in vehicle-treated rats, but decreased expression in the mGlu3-NAM group. Similar to the insular cortex, mGlu3-NAM reversed the stressor-induced upregulation of GriN3B in the BNST. mGlu3-NAM also upregulated GriN2A, GriN2B, GriN3B and Grm2 in the control group, but not the TMT group. Together, these data implicate mGlu3 receptor signaling in some lasting adaptations of predator odor stressor and anxiolytic-like effects.
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Affiliation(s)
- Ryan E Tyler
- Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Maya N Bluitt
- Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Julie L Engers
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA
| | - Craig W Lindsley
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA
| | - Joyce Besheer
- Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA; Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
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23
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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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Kumar S, Kumar SS. A Model for Predicting Cation Selectivity and Permeability in AMPA and NMDA Receptors Based on Receptor Subunit Composition. Front Synaptic Neurosci 2021; 13:779759. [PMID: 34912205 PMCID: PMC8667807 DOI: 10.3389/fnsyn.2021.779759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/04/2021] [Indexed: 11/13/2022] Open
Abstract
Glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) receptors are implicated in diverse functions ranging from synaptic plasticity to cell death. They are heterotetrameric proteins whose subunits are derived from multiple distinct gene families. The subunit composition of these receptors determines their permeability to monovalent and/or divalent cations, but it is not entirely clear how this selectivity arises in native and recombinantly-expressed receptor populations. By analyzing the sequence of amino acids lining the selectivity filters within the pore forming membrane helices (M2) of these subunits and by correlating subunit stoichiometry of these receptors with their ability to permeate Na+ and/or Ca2+, we propose here a mathematical model for predicting cation selectivity and permeability in these receptors. The model proposed is based on principles of charge attractivity and charge neutralization within the pore forming region of these receptors; it accurately predicts and reconciles experimental data across various platforms including Ca2+ permeability of GluA2-lacking AMPARs and ion selectivity within GluN3-containing di- and tri-heteromeric NMDARs. Additionally, the model provides insights into biophysical mechanisms regulating cation selectivity and permeability of these receptors and the role of various subunits in these processes.
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Affiliation(s)
- Sampath Kumar
- College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, United States
| | - Sanjay S Kumar
- Department of Biomedical Sciences, College of Medicine and Program in Neuroscience, Florida State University, Tallahassee, FL, United States
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25
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Sun Q, Cao W, Luo J. The roles of GluN3-containing N-methyl-D-aspartate receptor in central nerve system. Zhejiang Da Xue Xue Bao Yi Xue Ban 2021; 50:651-658. [PMID: 34986531 DOI: 10.3724/zdxbyxb-2021-0167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The N-methyl-D-aspartate receptor (NMDAR) in central nerve system is mostly composed of GluN1 and GluN2 subunits. The classical NMDAR has been intensively studied. However, GluN3‑containing NMDAR is much less expressed and have atypical channel properties. Recently, accumulating evidences have revealed two types of GluN3‑containing NMDAR: glutamate-gated GluN1/GluN2/GluN3 NMDAR and glycine-gated GluN1/GluN3 NMDAR. The former may play important roles in regulating synapse maturation and pruning non-used synapses, and its elevated expression at the adult stage may alter synaptic reorganization in some neuropsychiatric disorders. The latter is expressed in the medial habenula and involves in control of aversion. This article reviews the recent progresses on the expression, functional properties of GluN3‑containing atypical NMDARs and the physiological and pathological relevance.
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Affiliation(s)
- Qi Sun
- School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
| | - Wei Cao
- School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
| | - Jianhong Luo
- School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
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GluN3-Containing NMDA Receptors in the Rat Nucleus Accumbens Core Contribute to Incubation of Cocaine Craving. J Neurosci 2021; 41:8262-8277. [PMID: 34413203 DOI: 10.1523/jneurosci.0406-21.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 11/21/2022] Open
Abstract
Cue-induced cocaine craving progressively intensifies (incubates) after withdrawal from cocaine self-administration in rats and humans. In rats, the expression of incubation ultimately depends on Ca2+-permeable AMPARs that accumulate in synapses onto medium spiny neurons (MSNs) in the NAc core. However, the delay in their accumulation (∼1 month after drug self-administration ceases) suggests earlier waves of plasticity. This prompted us to conduct the first study of NMDAR transmission in NAc core during incubation, focusing on the GluN3 subunit, which confers atypical properties when incorporated into NMDARs, including insensitivity to Mg2+ block and Ca2+ impermeability. Whole-cell patch-clamp recordings were conducted in MSNs of adult male rats 1-68 d after discontinuing extended-access saline or cocaine self-administration. NMDAR transmission was enhanced after 5 d of cocaine withdrawal, and this persisted for at least 68 d of withdrawal. The earliest functional alterations were mediated through increased contributions of GluN2B-containing NMDARs, followed by increased contributions of GluN3-containing NMDARs. As predicted by GluN3-NMDAR incorporation, fewer MSN spines exhibited NMDAR-mediated Ca2+ entry. GluN3A knockdown in NAc core was sufficient to prevent incubation of craving, consistent with biotinylation studies showing increased GluN3A surface expression, although array tomography studies suggested that adaptations involving GluN3B also occur. Collectively, our data show that a complex cascade of NMDAR and AMPAR plasticity occurs in NAc core, potentially through a homeostatic mechanism, leading to persistent increases in cocaine cue reactivity and relapse vulnerability. This is a remarkable example of experience-dependent glutamatergic plasticity evolving over a protracted window in the adult brain.SIGNIFICANCE STATEMENT "Incubation of craving" is an animal model for the persistence of vulnerability to cue-induced relapse after prolonged drug abstinence. Incubation also occurs in human drug users. AMPAR plasticity in medium spiny neurons (MSNs) of the NAc core is critical for incubation of cocaine craving but occurs only after a delay. Here we found that AMPAR plasticity is preceded by NMDAR plasticity that is essential for incubation and involves GluN3, an atypical NMDAR subunit that markedly alters NMDAR transmission. Together with AMPAR plasticity, this represents profound remodeling of excitatory synaptic transmission onto MSNs. Given the importance of MSNs for translating motivation into action, this plasticity may explain, at least in part, the profound shifts in motivated behavior that characterize addiction.
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27
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Obolenskaya M, Dotsenko V, Martsenyuk O, Ralchenko S, Krupko O, Pastukhov A, Filimonova N, Starosila D, Chernykh S, Borisova T. A new insight into mechanisms of interferon alpha neurotoxicity: Expression of GRIN3A subunit of NMDA receptors and NMDA-evoked exocytosis. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110317. [PMID: 33785426 DOI: 10.1016/j.pnpbp.2021.110317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 10/21/2022]
Abstract
Neurological and psychiatric side effects accompany the high-dose interferon-alpha (IFNA) therapy. The primary genes responsible for these complications are mostly unknown. Our genome-wide search in mouse and rat genomes for the conservative genes containing IFN-stimulated response elements (ISRE) in their promoters revealed a new potential target gene of IFNA, Grin3α, which encodes the 3A subunit of NMDA receptor. This study aimed to explore the impact of IFNA on the expression of Grin3α and Ifnα genes and neurotransmitters endo/exocytosis in the mouse brain. We administered recombinant human IFN-alpha 2b (rhIFN-α2b) intracranially, and 24 h later, we isolated six brain regions and used the samples for RT-qPCR and western blot analysis. Synaptosomes were isolated from the cortex to analyze endo/exocytosis with acridine orange and L-[14C]glutamate. IFNA induced an increase in Grin3α mRNA and GRIN3A protein, but a decrease in Ifnα mRNA and protein. IFNA did not affect the accumulation and distribution of L-[14C]glutamate and acridine orange between synaptosomes and the extra-synaptosomal space. It caused the more significant acridine orange release activated by NMDA or glutamate than from control mice's synaptosomes. In response to IFNA, the newly discovered association between elevated Grin3α expression and NMDA- and glutamate-evoked neurotransmitters release from synaptosomes implies a new molecular mechanism of IFNA neurotoxicity.
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Affiliation(s)
- M Obolenskaya
- Laboratory of systems biology, Institute of molecular biology and genetics of the National Academy of Sciences of, Kyiv, Ukraine.
| | - V Dotsenko
- Laboratory of systems biology, Institute of molecular biology and genetics of the National Academy of Sciences of, Kyiv, Ukraine
| | - O Martsenyuk
- Laboratory of systems biology, Institute of molecular biology and genetics of the National Academy of Sciences of, Kyiv, Ukraine
| | - S Ralchenko
- Laboratory of systems biology, Institute of molecular biology and genetics of the National Academy of Sciences of, Kyiv, Ukraine
| | - O Krupko
- The Department of Neurochemistry, Palladin Institute of Biochemistry of the National Academy of Sciences of, Kyiv, Ukraine
| | - A Pastukhov
- The Department of Neurochemistry, Palladin Institute of Biochemistry of the National Academy of Sciences of, Kyiv, Ukraine
| | - N Filimonova
- Educational and scientific center "Institute of Biology, Taras Shevchenko National University of Kyiv, Ukraine
| | - D Starosila
- State Institution LV. Gromashevskiy Institute of Epidemiology and Infectious Diseases of the National Academy of Medical Sciences of, Kyiv, Ukraine
| | - S Chernykh
- Laboratory of systems biology, Institute of molecular biology and genetics of the National Academy of Sciences of, Kyiv, Ukraine
| | - T Borisova
- The Department of Neurochemistry, Palladin Institute of Biochemistry of the National Academy of Sciences of, Kyiv, Ukraine
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NMDA receptors elicit flux-independent intracellular Ca 2+ signals via metabotropic glutamate receptors and flux-dependent nitric oxide release in human brain microvascular endothelial cells. Cell Calcium 2021; 99:102454. [PMID: 34454368 DOI: 10.1016/j.ceca.2021.102454] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/28/2021] [Accepted: 08/12/2021] [Indexed: 12/20/2022]
Abstract
The excitatory neurotransmitter glutamate gates post-synaptic N-methyl-d-aspartate (NMDA) receptors (NMDARs) to mediate extracellular Ca2+ entry and stimulate neuronal nitric oxide (NO) synthase to release NO and trigger neurovascular coupling (NVC). Neuronal and glial NMDARs may also operate in a flux-independent manner, although it is unclear whether their non-ionotropic mode of action is involved in NVC. Recently, endothelial NMDARs were found to trigger Ca2+-dependent NO production and induce NVC, but the underlying mode of signaling remains elusive. Herein, we report that GluN1 protein, as well as GluN2C and GluN3B transcripts and proteins, were expressed and that NMDA did not elicit inward currents, but induced a dose-dependent increase in intracellular Ca2+ concentration ([Ca2+]i) in the human brain microvascular endothelial cell line, hCMEC/D3. A multidisciplinary approach, including live cell imaging, whole-cell patch-clamp recordings, pharmacological manipulation and gene targeting, revealed that NMDARs increase the [Ca2+]i in a flux-independent manner in hCMEC/D3 cells. The Ca2+ response to NMDA was triggered by endogenous Ca2+ release from the endoplasmic reticulum and the lysosomal Ca2+ stores and sustained by store-operated Ca2+ entry. Unexpectedly, pharmacological and genetic blockade of mGluR1 and mGluR5 dramatically impaired NMDARs-mediated Ca2+ signals. These findings indicate that NMDARs may increase the endothelial [Ca2+]i in a flux-independent manner via group 1 mGluRs. However, imaging of DAF-FM fluorescence revealed that NMDARs may also induce Ca2+-dependent NO release by signaling in a flux-dependent manner. These findings, therefore, shed novel light on the mechanisms whereby brain microvascular endothelium decodes glutamatergic signaling and regulates NVC.
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29
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Stroebel D, Mony L, Paoletti P. Glycine agonism in ionotropic glutamate receptors. Neuropharmacology 2021; 193:108631. [PMID: 34058193 DOI: 10.1016/j.neuropharm.2021.108631] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/21/2021] [Accepted: 05/23/2021] [Indexed: 12/12/2022]
Abstract
Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the vertebrate CNS. Classified as AMPA, kainate, delta and NMDA receptors, iGluRs are central drivers of synaptic plasticity widely considered as a major cellular substrate of learning and memory. Surprisingly however, five out of the eighteen vertebrate iGluR subunits do not bind glutamate but glycine, a neurotransmitter known to mediate inhibitory neurotransmission through its action on pentameric glycine receptors (GlyRs). This is the case of GluN1, GluN3A, GluN3B, GluD1 and GluD2 subunits, all also binding the D amino acid d-serine endogenously present in many brain regions. Glycine and d-serine action and affinities broadly differ between glycinergic iGluR subtypes. On 'conventional' GluN1/GluN2 NMDA receptors, glycine (or d-serine) acts in concert with glutamate as a mandatory co-agonist to set the level of receptor activity. It also regulates the receptor's trafficking and expression independently of glutamate. On 'unconventional' GluN1/GluN3 NMDARs, glycine acts as the sole agonist directly triggering opening of excitatory glycinergic channels recently shown to be physiologically relevant. On GluD receptors, d-serine on its own mediates non-ionotropic signaling involved in excitatory and inhibitory synaptogenesis, further reinforcing the concept of glutamate-insensitive iGluRs. Here we present an overview of our current knowledge on glycine and d-serine agonism in iGluRs emphasizing aspects related to molecular mechanisms, cellular function and pharmacological profile. The growing appreciation of the critical influence of glycine and d-serine on iGluR biology reshapes our understanding of iGluR signaling diversity and complexity, with important implications in neuropharmacology.
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Affiliation(s)
- David Stroebel
- Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM, F-75005, Paris, France.
| | - Laetitia Mony
- Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM, F-75005, Paris, France
| | - Pierre Paoletti
- Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM, F-75005, Paris, France.
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Crawley O, Conde-Dusman MJ, Pérez-Otaño I. GluN3A NMDA receptor subunits: more enigmatic than ever? J Physiol 2021; 600:261-276. [PMID: 33942912 DOI: 10.1113/jp280879] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/28/2021] [Indexed: 12/16/2022] Open
Abstract
Non-conventional N-methyl-d-aspartate receptors (NMDARs) containing GluN3A subunits have unique biophysical, signalling and localization properties within the NMDAR family, and are typically thought to counterbalance functions of classical NMDARs made up of GluN1/2 subunits. Beyond their recognized roles in synapse refinement during postnatal development, recent evidence is building a wider perspective for GluN3A functions. Here we draw particular attention to the latest developments for this multifaceted and unusual subunit: from finely timed expression patterns that correlate with plasticity windows in developing brains or functional hierarchies in the mature brain to new insight onto presynaptic GluN3A-NMDARs, excitatory glycine receptors and behavioural impacts, alongside further connections to a range of brain disorders.
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Affiliation(s)
- Oliver Crawley
- Unidad de Neurobiología Celular y de Sistemas, Instituto de Neurociencias (CSIC-UMH), San Juan de Alicante, 03550, Spain
| | - María J Conde-Dusman
- Unidad de Neurobiología Celular y de Sistemas, Instituto de Neurociencias (CSIC-UMH), San Juan de Alicante, 03550, Spain
| | - Isabel Pérez-Otaño
- Unidad de Neurobiología Celular y de Sistemas, Instituto de Neurociencias (CSIC-UMH), San Juan de Alicante, 03550, Spain
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31
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Pittaluga A. Presynaptic release-regulating NMDA receptors in isolated nerve terminals: A narrative review. Br J Pharmacol 2021; 178:1001-1017. [PMID: 33347605 PMCID: PMC9328659 DOI: 10.1111/bph.15349] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/10/2020] [Accepted: 12/03/2020] [Indexed: 02/02/2023] Open
Abstract
The existence of presynaptic, release‐regulating NMDA receptors in the CNS has been long matter of discussion. Most of the reviews dedicated to support this conclusion have preferentially focussed on the results from electrophysiological studies, paying little or no attention to the data obtained with purified synaptosomes, even though this experimental approach has been recognized as providing reliable information concerning the presence and the role of presynaptic release‐regulating receptors in the CNS. To fill the gap, this review is dedicated to summarising the results from studies with synaptosomes published during the last 40 years, which support the existence of auto and hetero NMDA receptors controlling the release of transmitters such as glutamate, GABA, dopamine, noradrenaline, 5‐HT, acetylcholine and peptides, in the CNS of mammals. The review also deals with the results from immunochemical studies in isolated nerve endings that confirm the functional observations.
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Affiliation(s)
- Anna Pittaluga
- Department of Pharmacology (DIFAR), School of Medical and Pharmaceutical Sciences, 3Rs Center, University of Genova, Italy.,San Martino Hospital IRCCS, Genova, Italy
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32
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Pagano J, Giona F, Beretta S, Verpelli C, Sala C. N-methyl-d-aspartate receptor function in neuronal and synaptic development and signaling. Curr Opin Pharmacol 2021; 56:93-101. [PMID: 33429227 DOI: 10.1016/j.coph.2020.12.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/01/2020] [Accepted: 12/04/2020] [Indexed: 02/08/2023]
Abstract
The N-methyl-d-aspartate (NMDA) receptor, among the ionotropic glutamate receptors, are fundamental to integrating and transducing complex signaling in neurons. Glutamate activation of these receptors mediates intracellular signals essential to neuronal and synaptic formation and synaptic plasticity and also contribute to excitotoxic processes in several neurological disorders. The NMDA receptor signaling is mediated by the permeability to Ca2+ and by the large network of signaling and scaffolding proteins associated mostly with the large C-terminal domain of GluN2 subunits. Important studies showed that GluN2 C-terminal interactions differ in accordance with the GluN2 subtype, and this influences the type of signaling that NMDA receptor activity controls. Thus, it is not surprising that mutations in genes that codify for NMDA receptor subunits have been associated with severe neuronal diseases. We will review recent advances and explore outstanding problems in this active area of research.
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Affiliation(s)
- Jessica Pagano
- CNR Neuroscience Institute, Milano and NeuroMi Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | - Federica Giona
- CNR Neuroscience Institute, Milano and NeuroMi Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | - Stefania Beretta
- CNR Neuroscience Institute, Milano and NeuroMi Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | - Chiara Verpelli
- CNR Neuroscience Institute, Milano and NeuroMi Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | - Carlo Sala
- CNR Neuroscience Institute, Milano and NeuroMi Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy.
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33
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Jorratt P, Hoschl C, Ovsepian SV. Endogenous antagonists of N-methyl-d-aspartate receptor in schizophrenia. Alzheimers Dement 2020; 17:888-905. [PMID: 33336545 DOI: 10.1002/alz.12244] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/24/2020] [Indexed: 12/28/2022]
Abstract
Schizophrenia is a chronic neuropsychiatric brain disorder that has devastating personal impact and rising healthcare costs. Dysregulation of glutamatergic neurotransmission has been implicated in the pathobiology of the disease, attributed largely to the hypofunction of the N-methyl-d-aspartate (NMDA) receptor. Currently, there is a major gap in mechanistic analysis as to how endogenous modulators of the NMDA receptors contribute to the onset and progression of the disease. We present a systematic review of the neurobiology and the role of endogenous NMDA receptor antagonists in animal models of schizophrenia, and in patients. We discuss their neurochemical origin, release from neurons and glia with action mechanisms, and functional effects, which might contribute toward the impairment of neuronal processes underlying this complex pathological state. We consider clinical evidence suggesting dysregulations of endogenous NMDA receptor in schizophrenia, and highlight the pressing need in future studies and emerging directions, to restore the NMDA receptor functions for therapeutic benefits.
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Affiliation(s)
- Pascal Jorratt
- Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czech Republic.,Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague 10, Czech Republic
| | - Cyril Hoschl
- Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czech Republic.,Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague 10, Czech Republic
| | - Saak V Ovsepian
- Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czech Republic.,Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague 10, Czech Republic
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34
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Murillo A, Navarro AI, Puelles E, Zhang Y, Petros TJ, Pérez-Otaño I. Temporal Dynamics and Neuronal Specificity of Grin3a Expression in the Mouse Forebrain. Cereb Cortex 2020; 31:1914-1926. [PMID: 33290502 PMCID: PMC7945027 DOI: 10.1093/cercor/bhaa330] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/13/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022] Open
Abstract
GluN3A subunits endow N-Methyl-D-Aspartate receptors (NMDARs) with unique biophysical, trafficking, and signaling properties. GluN3A-NMDARs are typically expressed during postnatal development, when they are thought to gate the refinement of neural circuits by inhibiting synapse maturation, and stabilization. Recent work suggests that GluN3A also operates in adult brains to control a variety of behaviors, yet a full spatiotemporal characterization of GluN3A expression is lacking. Here, we conducted a systematic analysis of Grin3a (gene encoding mouse GluN3A) mRNA expression in the mouse brain by combining high-sensitivity colorimetric and fluorescence in situ hybridization with labeling for neuronal subtypes. We find that, while Grin3a mRNA expression peaks postnatally, significant levels are retained into adulthood in specific brain regions such as the amygdala, medial habenula, association cortices, and high-order thalamic nuclei. The time-course of emergence and down-regulation of Grin3a expression varies across brain region, cortical layer of residence, and sensory modality, in a pattern that correlates with previously reported hierarchical gradients of brain maturation and functional specialization. Grin3a is expressed in both excitatory and inhibitory neurons, with strong mRNA levels being a distinguishing feature of somatostatin interneurons. Our study provides a comprehensive map of Grin3a distribution across the murine lifespan and paves the way for dissecting the diverse functions of GluN3A in health and disease.
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Affiliation(s)
- Alvaro Murillo
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas - Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.,UK Dementia Research Institute at Cardiff University, CF24 4HQ Cardiff, UK
| | - Ana I Navarro
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas - Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain
| | - Eduardo Puelles
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas - Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain
| | - Yajun Zhang
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Timothy J Petros
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Isabel Pérez-Otaño
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas - Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain
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35
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Wong HHW, Rannio S, Jones V, Thomazeau A, Sjöström PJ. NMDA receptors in axons: there's no coincidence. J Physiol 2020; 599:367-387. [PMID: 33141440 DOI: 10.1113/jp280059] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/27/2020] [Indexed: 12/16/2022] Open
Abstract
In the textbook view, N-methyl-d-aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short-term and long-term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse-type-specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident.
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Affiliation(s)
- Hovy Ho-Wai Wong
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
| | - Sabine Rannio
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
| | - Victoria Jones
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
| | - Aurore Thomazeau
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
| | - P Jesper Sjöström
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
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36
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Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions. Int J Mol Sci 2020; 21:ijms21217951. [PMID: 33114753 PMCID: PMC7662754 DOI: 10.3390/ijms21217951] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/19/2020] [Accepted: 10/23/2020] [Indexed: 02/08/2023] Open
Abstract
Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.
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37
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Zhu Z, Yi F, Epplin MP, Liu D, Summer SL, Mizu R, Shaulsky G, XiangWei W, Tang W, Burger PB, Menaldino DS, Myers SJ, Liotta DC, Hansen KB, Yuan H, Traynelis SF. Negative allosteric modulation of GluN1/GluN3 NMDA receptors. Neuropharmacology 2020; 176:108117. [PMID: 32389749 DOI: 10.1016/j.neuropharm.2020.108117] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 04/14/2020] [Accepted: 04/27/2020] [Indexed: 12/15/2022]
Abstract
NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission. Most native NMDA receptors are tetrameric assemblies of two glycine-binding GluN1 and two glutamate-binding GluN2 subunits. Co-assembly of the glycine-binding GluN1 with glycine-binding GluN3 subunits (GluN3A-B) creates glycine activated receptors that possess strikingly different functional and pharmacological properties compared to GluN1/GluN2 NMDA receptors. The role of GluN1/GluN3 receptors in neuronal function remains unknown, in part due to lack of pharmacological tools with which to explore their physiological roles. We have identified the negative allosteric modulator EU1180-438, which is selective for GluN1/GluN3 receptors over GluN1/GluN2 NMDA receptors, AMPA, and kainate receptors. EU1180-438 is also inactive at GABA, glycine, and P2X receptors, but displays inhibition of some nicotinic acetylcholine receptors. Furthermore, we demonstrate that EU1180-438 produces robust inhibition of glycine-activated current responses mediated by native GluN1/GluN3A receptors in hippocampal CA1 pyramidal neurons. EU1180-438 is a non-competitive antagonist with activity that is independent of membrane potential (i.e. voltage-independent), glycine concentration, and extracellular pH. Non-stationary fluctuation analysis of neuronal current responses provided an estimated weighted mean unitary conductance of 6.1 pS for GluN1/GluN3A channels, and showed that EU1180-438 has no effect on conductance. Site-directed mutagenesis suggests that structural determinants of EU1180-438 activity reside near a short pre-M1 helix that lies parallel to the plane of the membrane below the agonist binding domain. These findings demonstrate that structural differences between GluN3 and other glutamate receptor subunits can be exploited to generate subunit-selective ligands with utility in exploring the roles GluN3 in neuronal function.
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Affiliation(s)
- Zongjian Zhu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA; Department of Neonatology, First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Feng Yi
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Matthew P Epplin
- Department of Chemistry, Emory University, Atlanta, GA, 30322, USA
| | - Ding Liu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | | | - Ruth Mizu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Gil Shaulsky
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Wenshu XiangWei
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Weiting Tang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Pieter B Burger
- Department of Chemistry, Emory University, Atlanta, GA, 30322, USA
| | | | - Scott J Myers
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Dennis C Liotta
- Department of Chemistry, Emory University, Atlanta, GA, 30322, USA
| | - Kasper B Hansen
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Hongjie Yuan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Stephen F Traynelis
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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38
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Belov Kirdajova D, Kriska J, Tureckova J, Anderova M. Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells. Front Cell Neurosci 2020; 14:51. [PMID: 32265656 PMCID: PMC7098326 DOI: 10.3389/fncel.2020.00051] [Citation(s) in RCA: 232] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/21/2020] [Indexed: 12/21/2022] Open
Abstract
A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is a prominent cause of death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose and oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion and ionic imbalance, followed by cell membrane depolarization, calcium (Ca2+) overload, and extracellular accumulation of excitatory amino acid glutamate. If tight physiological regulation fails to clear the surplus of this neurotransmitter, subsequent prolonged activation of glutamate receptors forms a vicious circle between elevated concentrations of intracellular Ca2+ ions and aberrant glutamate release, aggravating the effect of this ischemic pathway. The activation of downstream Ca2+-dependent enzymes has a catastrophic impact on nervous tissue leading to cell death, accompanied by the formation of free radicals, edema, and inflammation. After decades of “neuron-centric” approaches, recent research has also finally shed some light on the role of glial cells in neurological diseases. It is becoming more and more evident that neurons and glia depend on each other. Neuronal cells, astrocytes, microglia, NG2 glia, and oligodendrocytes all have their roles in what is known as glutamate excitotoxicity. However, who is the main contributor to the ischemic pathway, and who is the unsuspecting victim? In this review article, we summarize the so-far-revealed roles of cells in the central nervous system, with particular attention to glial cells in ischemia-induced glutamate excitotoxicity, its origins, and consequences.
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Affiliation(s)
- Denisa Belov Kirdajova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia.,Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Jan Kriska
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia.,Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Jana Tureckova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia
| | - Miroslava Anderova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia.,Second Faculty of Medicine, Charles University, Prague, Czechia
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Kohlmeier KA, Polli FS. Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function. Front Synaptic Neurosci 2020; 12:3. [PMID: 32116639 PMCID: PMC7019863 DOI: 10.3389/fnsyn.2020.00003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/14/2020] [Indexed: 12/16/2022] Open
Abstract
The brainstem has traditionally been considered an area of the brain with autonomous control of mostly homeostatic functions such as heart rate, respiration, and the sleep and wakefulness state, which would preclude the necessity to exhibit the high degree of synaptic or cellular mechanisms of plasticity typical of regions of the brain responsible for flexible, executive control, such as the medial prefrontal cortex or the hippocampus. The perception that the brainstem does not share the same degree of flexibility to alter synaptic strength and/or wiring within local circuits makes intuitive sense, as it is not easy to understand how "soft wiring" would be an advantage when considering the importance of faithful and consistent performance of the homeostatic, autonomic functions that are controlled by the brainstem. However, many of the molecular and cellular requirements which underlie strengthening of synapses seen in brain regions involved in higher-level processing are present in brainstem nuclei, and recent research suggest that the view of the brainstem as "hard wired," with rigid and static connectivity and with unchanging synaptic strength, is outdated. In fact, information from studies within the last decades, including work conducted in our group, leads us to propose that the brainstem can dynamically alter synaptic proteins, and change synaptic connections in response to prenatal or postnatal stimuli, and this would likely alter functionality and output. This article reviews recent research that has provided information resulting in our revision of the view of the brainstem as static and non-changing by using as example recent information gleaned from a brainstem pontine nucleus, the laterodorsal tegmentum (LDT). The LDT has demonstrated mechanisms underlying synaptic plasticity, and plasticity has been exhibited in the postnatal LDT following exposure to drugs of abuse. Further, exposure of the brain during gestation to drugs of abuse results in alterations in development of signaling pathways in the LDT. As the LDT provides a high degree of innervation of mesoaccumbal and mesocortical circuits involved in salience, as well as thalamocortical circuits involved in control of arousal and orientation, changes in synaptic strength would be expected to alter output, which would significantly impact behavioral state, motivated behavior and directed attention. Further, alterations in developmental trajectory within the LDT following prenatal exposure to drugs of abuse would be expected to impact on later life expression of motivation and arousal.
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Affiliation(s)
- Kristi A. Kohlmeier
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
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40
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Chen J, Liu Q, Fan R, Han H, Yang Z, Cui W, Song G, Li MD. Demonstration of critical role of GRIN3A in nicotine dependence through both genetic association and molecular functional studies. Addict Biol 2020; 25:e12718. [PMID: 30741440 DOI: 10.1111/adb.12718] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/19/2018] [Accepted: 01/08/2019] [Indexed: 11/27/2022]
Abstract
Nicotine dependence (ND) is a chronic disease with catastrophic effects on individual and public health. The glutamate receptor subunit gene, ionotropic N-methyl-d-aspartate 3A (GRIN3A), encodes a crucial subunit of N-methyl-d-aspartate receptors (NMDARs), which play an essential role in synaptic plasticity in the brain. Although various variants of GRIN3A have been associated with ND in European-American and African-American samples, no study has been reported for the association between GRIN3A and ND in Chinese Han population. We performed an association study of 16 single nucleotide polymorphisms (SNPs) in GRIN3A with ND in 2616 Chinese individuals. SNP-based association analysis indicated that SNP rs1323423 was significantly associated with the Fagerström Test for Nicotine Dependence (FTND) score after correction for multiple testing (P = 0.0026). Haplotype-based association analysis revealed that Block 3, formed by rs1323423-rs10989591, was significantly associated with the FTND score after correction for multiple testing (global P = 0.0183). Furthermore, luciferase reporter assay demonstrated that the DNA region containing rs1323423 was an enhancer element, the activity of which was significantly impacted by rs1323423 genotype. Considering that rs1323423 is located in a potential enhancer region, we performed GRIN3A editing in HEK293T cells with CRISPR/Cas9 and found that the DNA region around rs1323423 has a regulatory function and the expression of GRIN3A affects the expression of other NMDA subunits. Moreover, we demonstrated that nicotine at a concentration of 100 μM decreased expression of GRIN3A in SH-SY5Y and HEK293T cells at the RNA and protein level, respectively. This study provides novel evidence for the involvement of GRIN3A in ND.
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Affiliation(s)
- Jiali Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesZhejiang University School of Medicine China
| | - Qiang Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesZhejiang University School of Medicine China
| | - Rongli Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesZhejiang University School of Medicine China
| | - Haijun Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesZhejiang University School of Medicine China
| | - Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesZhejiang University School of Medicine China
| | - Wenyan Cui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesZhejiang University School of Medicine China
| | - Guohua Song
- Animal Research CenterShanxi Medical University China
| | - Ming D. Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesZhejiang University School of Medicine China
- Research Center for Air Pollution and HealthZhejiang University China
- Institute of NeuroImmune PharmacologySeton Hall University South Orange New Jersey USA
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41
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Goldsmith PJ. NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites. Curr Top Med Chem 2019; 19:2239-2253. [PMID: 31660834 DOI: 10.2174/1568026619666191011095341] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/30/2019] [Accepted: 09/06/2019] [Indexed: 12/16/2022]
Abstract
The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.
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Affiliation(s)
- Paul J Goldsmith
- Eli Lilly and Co. Ltd, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, United Kingdom
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Circuit-specific control of the medial entorhinal inputs to the dentate gyrus by atypical presynaptic NMDARs activated by astrocytes. Proc Natl Acad Sci U S A 2019; 116:13602-13610. [PMID: 31152131 PMCID: PMC6612919 DOI: 10.1073/pnas.1816013116] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Here, we investigated the properties of presynaptic N-methyl-d-aspartate receptors (pre-NMDARs) at corticohippocampal excitatory connections between perforant path (PP) afferents and dentate granule cells (GCs), a circuit involved in memory encoding and centrally affected in Alzheimer's disease and temporal lobe epilepsy. These receptors were previously reported to increase PP release probability in response to gliotransmitters released from astrocytes. Their activation occurred even under conditions of elevated Mg2+ and lack of action potential firing in the axons, although how this could be accomplished was unclear. We now report that these pre-NMDARs contain the GluN3a subunit conferring them low Mg2+ sensitivity. GluN3a-containing NMDARs at PP-GC synapses are preponderantly presynaptic vs. postsynaptic and persist beyond the developmental period. Moreover, they are expressed selectively at medial-not lateral-PP axons and act to functionally enhance release probability specifically of the medial perforant path (MPP) input to GC dendrites. By controlling release probability, GluN3a-containing pre-NMDARs also control the dynamic range for long-term potentiation (LTP) at MPP-GC synapses, an effect requiring Ca2+ signaling in astrocytes. Consistent with the functional observations, GluN3a subunits in MPP terminals are localized at sites away from the presynaptic release sites, often facing astrocytes, in line with a primary role for astrocytic inputs in their activation. Overall, GluN3A-containing pre-NMDARs emerge as atypical modulators of dendritic computations in the MPP-GC memory circuit.
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Su T, Lu Y, Geng Y, Lu W, Chen Y. How could N-Methyl-D-Aspartate Receptor Antagonists Lead to Excitation Instead of Inhibition? BRAIN SCIENCE ADVANCES 2019. [DOI: 10.26599/bsa.2018.2018.9050009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
N-methyl-D-aspartate receptors (NMDARs) are a family of ionotropic glutamate receptors mainly known to mediate excitatory synaptic transmission and plasticity. Interestingly, low-dose NMDAR antagonists lead to increased, instead of decreased, functional connectivity; and they could cause schizophrenia- and/or antidepressant-like behavior in both humans and rodents. In addition, human genetic evidences indicate that NMDAR loss of function mutations underlie certain forms of epilepsy, a disease featured with abnormal brain hyperactivity. Together, they all suggest that under certain conditions, NMDAR activation actually lead to inhibition, but not excitation, of the global neuronal network. Apparently, these phenomena are rather counterintuitive to the receptor's basic role in mediating excitatory synaptic transmission. How could it happen? Recently, this has become a crucial question in order to fully understand the complexity of NMDAR function, particularly in disease. Over the past decades, different theories have been proposed to address this question. These include theories of “NMDARs on inhibitory neurons are more sensitive to antagonism”, or “basal NMDAR activity actually inhibits excitatory synapse”, etc. Our review summarizes these efforts, and also provides an introduction of NMDARs, inhibitory neurons, and their relationships with the related diseases. Advances in the development of novel NMDAR pharmacological tools, particularly positive allosteric modulators, are also included to provide insights into potential intervention strategies.
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Affiliation(s)
- Tonghui Su
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yi Lu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yang Geng
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wei Lu
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yelin Chen
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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Abstract
Pain management is complex regardless of whether the pain is acute or chronic in nature or non-cancer or cancer related. In addition, relatively few pain pharmacotherapy options with adequate efficacy and safety data currently exist. Consequently, interest in the role of NMDA receptor antagonists as a pharmacological pain management strategy has surfaced. This narrative review provides an overview of the NMDA receptor and elaborates on the pharmacotherapeutic profile and pain management literature findings for the following NMDA receptor antagonists: ketamine, memantine, dextromethorphan, and magnesium. The literature on this topic is characterized by small studies, many of which exhibit methodological flaws. To date, ketamine is the most studied NMDA receptor antagonist for both acute and chronic pain management. Although further research about NMDA receptor antagonists for analgesia is needed and the optimal dosage/administration regimens for these drugs have yet to be determined, ketamine appears to hold the most promise and may be of particular value in the perioperative pain management realm.
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Atoji Y, Sarkar S. Gene expression of AMPA, kainate, and NMDA receptor subunits in the pigeon spinal cord. J Chem Neuroanat 2019; 96:148-156. [DOI: 10.1016/j.jchemneu.2018.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 11/01/2018] [Accepted: 12/07/2018] [Indexed: 10/27/2022]
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Liu J, Chang L, Song Y, Li H, Wu Y. The Role of NMDA Receptors in Alzheimer's Disease. Front Neurosci 2019; 13:43. [PMID: 30800052 PMCID: PMC6375899 DOI: 10.3389/fnins.2019.00043] [Citation(s) in RCA: 297] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/16/2019] [Indexed: 12/13/2022] Open
Abstract
In Alzheimer’s disease (AD), early synaptic dysfunction is associated with the increased oligomeric amyloid-beta peptide, which causes NMDAR-dependent synaptic depression and spine elimination. Memantine, low-affinity NMDAR channel blocker, has been used in the treatment of moderate to severe AD. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between NMDARs dysfunction and AD. This review focuses on not only changes in expression of different NMDAR subunits, but also some unconventional modes of NMDAR action.
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Affiliation(s)
- Jinping Liu
- School of Medicine, Tsinghua University, Beijing, China
| | - Lirong Chang
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Yizhi Song
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Hui Li
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Yan Wu
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
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Skowrońska K, Obara-Michlewska M, Zielińska M, Albrecht J. NMDA Receptors in Astrocytes: In Search for Roles in Neurotransmission and Astrocytic Homeostasis. Int J Mol Sci 2019; 20:ijms20020309. [PMID: 30646531 PMCID: PMC6358855 DOI: 10.3390/ijms20020309] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 01/08/2019] [Accepted: 01/10/2019] [Indexed: 12/15/2022] Open
Abstract
Studies of the last two decades have demonstrated the presence in astrocytic cell membranes of N-methyl-d-aspartate (NMDA) receptors (NMDARs), albeit their apparently low abundance makes demonstration of their presence and function more difficult than of other glutamate (Glu) receptor classes residing in astrocytes. Activation of astrocytic NMDARs directly in brain slices and in acutely isolated or cultured astrocytes evokes intracellular calcium increase, by mutually unexclusive ionotropic and metabotropic mechanisms. However, other than one report on the contribution of astrocyte-located NMDARs to astrocyte-dependent modulation of presynaptic strength in the hippocampus, there is no sound evidence for the significant role of astrocytic NMDARs in astrocytic-neuronal interaction in neurotransmission, as yet. Durable exposure of astrocytic and neuronal co-cultures to NMDA has been reported to upregulate astrocytic synthesis of glutathione, and in this way to increase the antioxidative capacity of neurons. On the other hand, overexposure to NMDA decreases, by an as yet unknown mechanism, the ability of cultured astrocytes to express glutamine synthetase (GS), aquaporin-4 (AQP4), and the inward rectifying potassium channel Kir4.1, the three astroglia-specific proteins critical for homeostatic function of astrocytes. The beneficial or detrimental effects of astrocytic NMDAR stimulation revealed in the in vitro studies remain to be proven in the in vivo setting.
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Affiliation(s)
- Katarzyna Skowrońska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
| | - Marta Obara-Michlewska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
| | - Jan Albrecht
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
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Keith RE, Azcarate JM, Keith MJ, Hung CW, Badakhsh MF, Dumas TC. Direct Intracellular Signaling by the Carboxy terminus of NMDA Receptor GluN2 Subunits Regulates Dendritic Morphology in Hippocampal CA1 Pyramidal Neurons. Neuroscience 2019; 396:138-153. [PMID: 30471357 PMCID: PMC6311441 DOI: 10.1016/j.neuroscience.2018.11.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 10/16/2018] [Accepted: 11/14/2018] [Indexed: 12/22/2022]
Abstract
N-methyl-d-aspartate receptors (NMDARs) are glutamatergic receptors that take part in excitatory synaptic transmission and drive functional and structural neuronal plasticity, including activity-dependent changes in dendritic morphology. Forebrain NMDARs contribute to neuronal plasticity in at least two ways: through calcium-mediated processes or via direct intracellular postsynaptic signaling. Both properties are regulated by the GluN2 subunits. However, the separate contributions of these properties to the regulation of dendritic morphology are unknown. We created transgenic mice that express chimeric GluN2 subunits and examined the impact on pyramidal cell dendritic morphology in hippocampal region CA1. Golgi-Cox impregnation and transgenic expression of green fluorescent protein were employed to visualize dendritic arbors. In adult mice with a predominantly native GluN2A background, overexpression of the GluN2B carboxy terminus increased the total path of the dendritic arbor without affecting branch number or tortuosity. Overexpressing the amino terminus and transmembrane domains of GluN2B had little effect. It may be inferred from these results that NMDAR-dependent intracellular signaling regulates dendritic morphology of hippocampal pyramidal cells more so than calcium conductance dynamics. The findings add to the understanding of NMDAR-mediated signaling in hippocampal neurons and support re-investigation of the molecular underpinnings of NMDAR involvement in postnatal dendrite maturation.
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Affiliation(s)
- Rachel E Keith
- Interdisciplinary Program in Neuroscience, George Mason University, Fairfax, VA 22030, United States; Krasnow Institute of Advanced Study, George Mason University, Fairfax, VA 22030, United States
| | - Jessica M Azcarate
- Krasnow Institute of Advanced Study, George Mason University, Fairfax, VA 22030, United States
| | - Matthew J Keith
- Krasnow Institute of Advanced Study, George Mason University, Fairfax, VA 22030, United States
| | - Carey W Hung
- Krasnow Institute of Advanced Study, George Mason University, Fairfax, VA 22030, United States
| | - Maryam F Badakhsh
- Krasnow Institute of Advanced Study, George Mason University, Fairfax, VA 22030, United States
| | - Theodore C Dumas
- Psychology Department, George Mason University, Fairfax, VA 22030, United States; Interdisciplinary Program in Neuroscience, George Mason University, Fairfax, VA 22030, United States; Krasnow Institute of Advanced Study, George Mason University, Fairfax, VA 22030, United States.
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Kuzmina US, Zainullina LF, Vakhitov VA, Bakhtiyarova KZ, Vakhitova YV. The role of glutamate in the pathogenesis of multiple sclerosis. Zh Nevrol Psikhiatr Im S S Korsakova 2019; 119:160-167. [DOI: 10.17116/jnevro2019119081160] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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50
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Abstract
GluN3A and GluN3B are glycine-binding subunits belonging to the NMDA receptor (NMDAR) family that can assemble with the GluN1 subunit to form unconventional receptors activated by glycine alone. Functional characterization of GluN1/GluN3 NMDARs has been difficult. Here, we uncover two modalities that have transformative properties on GluN1/GluN3A receptors. First, we identify a compound, CGP-78608, which greatly enhances GluN1/GluN3A responses, converting small and rapidly desensitizing currents into large and stable responses. Second, we show that an endogenous GluN3A disulfide bond endows GluN1/GluN3A receptors with distinct redox modulation, profoundly affecting agonist sensitivity and gating kinetics. Under reducing conditions, ambient glycine is sufficient to generate tonic receptor activation. Finally, using CGP-78608 on P8-P12 mouse hippocampal slices, we demonstrate that excitatory glycine GluN1/GluN3A NMDARs are functionally expressed in native neurons, at least in the juvenile brain. Our work opens new perspectives on the exploration of excitatory glycine receptors in brain function and development. Excitatory glycine GluN1/GluN3A receptors are atypical NMDARs that have been difficult to study. Here the authors identify new properties of these receptors, including potentiation by the GluN1 antagonist CGP-78608 that allows detection of functional GluN1/GluN3A receptors in the juvenile brain.
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