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Srivastava I, Goikolea J, Ayberk Kaya T, Latorre-Leal M, Eroli F, Pereira Iglesias M, Álvarez-Jiménez L, Arroyo-García LE, Shimozawa M, Nilsson P, Fisahn A, Lindskog M, Maioli S, Loera-Valencia R. Reactive Astrocytes with Reduced Function of Glutamate Transporters in the AppNL-G-F Knock-in Mice. ACS Chem Neurosci 2025. [PMID: 40421586 DOI: 10.1021/acschemneuro.4c00714] [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: 05/28/2025] Open
Abstract
Alzheimer's disease (AD) is associated with synaptic and memory dysfunction. One of the hallmarks of AD is reactive astrogliosis, with reactive astrocytes surrounding amyloid plaques in the brain. Astrocytes have also been shown to be actively involved in disease progression, nevertheless, mechanistic information about their role in synaptic transmission during AD pathology is lacking. Astrocytes maintain synaptic transmission by taking up extracellular glutamate during synaptic activity through astrocytic glutamate transporter GLT-1, but its function has been difficult to measure in real-time in AD pathology. Here, we used an App knock-in AD model (AppNL-G-F) carrying the Swedish, Arctic and Beyreuther mutations associated with AD and exhibiting AD-like Aβ plaque deposition and memory impairment. Using immunohistochemistry, patch-clamp of astrocytes, and Western blot from tissue and FACS isolated synaptosomes, we found that AppNL-G-F mice at 6-8 months of age have astrocytes with clearly altered morphology compared to wild-type (WT). Moreover, astrocyte glutamate clearance function in AppNL-G-F mice, measured as electrophysiological recordings of glutamate transporter currents, was severely impaired compared to WT animals. The reduction of glutamate uptake by astrocytes cannot be explained by GLT-1 protein levels, which were unchanged in synaptosomes and hippocampus of AppNL-G-F mice. Our data suggest that astrocytic glutamate transporters are affected by excess Aβ42 in the brain contributing to synaptic dysfunction in the hippocampus. This data contributes to the notion of restoring astrocyte synaptic function as a potential therapeutic strategy to treat AD.
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Affiliation(s)
- Ipsit Srivastava
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Julen Goikolea
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Tamer Ayberk Kaya
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - María Latorre-Leal
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Francesca Eroli
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Marta Pereira Iglesias
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Laura Álvarez-Jiménez
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Luis Enrique Arroyo-García
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Makoto Shimozawa
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Per Nilsson
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - André Fisahn
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Maria Lindskog
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Silvia Maioli
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
| | - Raúl Loera-Valencia
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Campus Chihuahua, Av. H. Colegio Militar 4700, Nombre de Dios, 31150 Chihuahua, Chih. Mexico
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Martinez-Lozada Z, Guillem AM, Song I, Gonzalez MV, Takano H, Parikh E, Rothstein JD, Putt ME, Robinson MB. Identification of a Subpopulation of Astrocyte Progenitor Cells in the Neonatal Subventricular Zone: Evidence that Migration is Regulated by Glutamate Signaling. Neurochem Res 2025; 50:77. [PMID: 39789409 PMCID: PMC11717811 DOI: 10.1007/s11064-024-04326-2] [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: 09/27/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 01/12/2025]
Abstract
In mice engineered to express enhanced green fluorescent protein (eGFP) under the control of the entire glutamate transporter 1 (GLT1) gene, eGFP is found in all 'adult' cortical astrocytes. However, when 8.3 kilobases of the human GLT1/EAAT2 promoter is used to control expression of tdTomato (tdT), tdT is only found in a subpopulation of these eGFP-expressing astrocytes. The eGFP mice have been used to define mechanisms of transcriptional regulation using astrocytes cultured from cortex of 1-3 day old mice. Using the same cultures, we were never able to induce tdT+ expression. We hypothesized that these cells might not have migrated into the cortex by this age. In this study, we characterized the ontogeny of tdT+ cells, performed single-cell RNA sequencing (scRNA-seq), and tracked their migration in organotypic slice cultures. At postnatal day (PND) 1, tdT+ cells were observed in the subventricular zone and striatum but not in the cortex, and they did not express eGFP. At PND7, tdT+ cells begin to appear in the cortex with their numbers increasing with age. At PND1, scRNA-seq demonstrates that the tdT+ cells are molecularly heterogeneous, with a subpopulation expressing astrocytic markers, subsequently validated with immunofluorescence. In organotypic slices, tdT+ cells migrate into the cortex, and after 7 days they express GLT1, NF1A, and eGFP. An ionotropic glutamate receptor (iGluR) antagonist reduced by 50% the distance tdT+ cells migrate from the subventricular zone into the cortex. The pan-glutamate transport inhibitor, TFB-TBOA, increased, by sixfold, the number of tdT+ cells in the cortex. In conclusion, although tdT is expressed by non-glial cells at PND1, it is also expressed by glial progenitors that migrate into the cortex postnatally. Using this fluorescent labeling, we provide novel evidence that glutamate signaling contributes to the control of glial precursor migration.
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Affiliation(s)
- Zila Martinez-Lozada
- Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104-4318, USA.
- Department of Neuroscience, College of Psychology and Neuroscience, Nova Southeastern University, Fort Lauderdale, FL, 33328, USA.
| | - Alain M Guillem
- Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
| | - Isabella Song
- Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
| | - Michael V Gonzalez
- Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Hajime Takano
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Esha Parikh
- Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104-4318, USA
| | - Jeffrey D Rothstein
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Mary E Putt
- Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Michael B Robinson
- Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104-4318, USA.
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3
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Blaylock RL. Additive aluminum as a cause of induced immunoexcitoxicity resulting in neurodevelopmental and neurodegenerative disorders: A biochemical, pathophysiological, and pharmacological analysis. Surg Neurol Int 2024; 15:171. [PMID: 38840623 PMCID: PMC11152537 DOI: 10.25259/sni_296_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 06/07/2024] Open
Abstract
Much has been learned about the neurotoxicity of aluminum over the past several decades in terms of its ability to disrupt cellular function, result in slow accumulation, and the difficulty of its removal from cells. Newer evidence suggests a central pathophysiological mechanism may be responsible for much of the toxicity of aluminum and aluminofluoride compounds on the brain and spinal cord. This mechanism involves activation of the brain's innate immune system, primarily the microglia, astrocytes, and macrophages, with a release of neurotoxic concentrations of excitotoxins and proinflammatory cytokines, chemokines, and immune mediators. Many studies suggest that excitotoxicity plays a significant role in the neurotoxic action of several metals, including aluminum. Recently, researchers have found that while most of the chronic pathology involved in the observed neurodegenerative effects of these metals are secondary to prolonged inflammation, it is the enhancement of excitotoxicity by the immune mediators that are responsible for most of the metal's toxicity. This enhancement occurs through a crosstalk between cytokines and glutamate-related mechanisms. The author coined the name immunoexcitotoxicity to describe this process. This paper reviews the evidence linking immunoexcitotoxicity to aluminum's neurotoxic effects and that a slow accumulation of aluminum may be the cause of neurodevelopmental defects as well as neurodegeneration in the adult.
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Affiliation(s)
- Russell L. Blaylock
- Theoretical Neuroscience Research, LLC, Ridgeland, Mississippi, United States
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4
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Xing L, Gkini V, Nieminen AI, Zhou HC, Aquilino M, Naumann R, Reppe K, Tanaka K, Carmeliet P, Heikinheimo O, Pääbo S, Huttner WB, Namba T. Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development. Nat Commun 2024; 15:3468. [PMID: 38658571 PMCID: PMC11043075 DOI: 10.1038/s41467-024-47437-8] [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: 11/03/2023] [Accepted: 04/02/2024] [Indexed: 04/26/2024] Open
Abstract
Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B's ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.
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Affiliation(s)
- Lei Xing
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
- Department of Biological Sciences, University of Manitoba, Winnipeg, MB, Canada.
| | - Vasiliki Gkini
- Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Anni I Nieminen
- FIMM Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Hui-Chao Zhou
- Center for Cancer Biology (CCB), VIB-KU Leuven, B-3000, Leuven, Belgium
| | - Matilde Aquilino
- Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Ronald Naumann
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Katrin Reppe
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Kohichi Tanaka
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, B-3000, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, B-3000, Leuven, Belgium
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Oskari Heikinheimo
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Svante Pääbo
- Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
- Human Evolutionary Genomics Unit, Okinawa Institute of Science and Technology, Okinawa, Onna-son, Japan
| | - Wieland B Huttner
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
| | - Takashi Namba
- Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
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5
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Perez-Ramirez CA, Nakano H, Law RC, Matulionis N, Thompson J, Pfeiffer A, Park JO, Nakano A, Christofk HR. Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy. Cell 2024; 187:204-215.e14. [PMID: 38070508 PMCID: PMC10843853 DOI: 10.1016/j.cell.2023.11.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/27/2023] [Accepted: 11/08/2023] [Indexed: 01/07/2024]
Abstract
Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.
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Affiliation(s)
- Cesar A Perez-Ramirez
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA
| | - Haruko Nakano
- Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA
| | - Richard C Law
- Department of Chemical and Biomolecular Engineering, UCLA, Los Angeles, CA 90095, USA
| | - Nedas Matulionis
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Jennifer Thompson
- Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA
| | - Andrew Pfeiffer
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Junyoung O Park
- Department of Chemical and Biomolecular Engineering, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA
| | - Atsushi Nakano
- Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
| | - Heather R Christofk
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
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6
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Silva-Parra J, Sandu C, Felder-Schmittbuhl MP, Hernández-Kelly LC, Ortega A. Aryl Hydrocarbon Receptor in Glia Cells: A Plausible Glutamatergic Neurotransmission Orchestrator. Neurotox Res 2023; 41:103-117. [PMID: 36607593 DOI: 10.1007/s12640-022-00623-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/23/2022] [Accepted: 12/15/2022] [Indexed: 01/07/2023]
Abstract
Glutamate is the major excitatory amino acid in the vertebrate brain. Glutamatergic signaling is involved in most of the central nervous system functions. Its main components, namely receptors, ion channels, and transporters, are tightly regulated at the transcriptional, translational, and post-translational levels through a diverse array of extracellular signals, such as food, light, and neuroactive molecules. An exquisite and well-coordinated glial/neuronal bidirectional communication is required for proper excitatory amino acid signal transactions. Biochemical shuttles such as the glutamate/glutamine and the astrocyte-neuronal lactate represent the fundamental involvement of glial cells in glutamatergic transmission. In fact, the disruption of any of these coordinated biochemical intercellular cascades leads to an excitotoxic insult that underlies some aspects of most of the neurodegenerative diseases characterized thus far. In this contribution, we provide a comprehensive summary of the involvement of the Aryl hydrocarbon receptor, a ligand-dependent transcription factor in the gene expression regulation of glial glutamate transporters. These receptors might serve as potential targets for the development of novel strategies for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Janisse Silva-Parra
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, 07360, CDMX, México
| | - Cristina Sandu
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France
| | - Marie-Paule Felder-Schmittbuhl
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France
| | - Luisa C Hernández-Kelly
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, 07360, CDMX, México
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, 07360, CDMX, México.
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7
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Kaul D, Schwab SG, Mechawar N, Ooi L, Matosin N. Alterations in Astrocytic Regulation of Excitation and Inhibition by Stress Exposure and in Severe Psychopathology. J Neurosci 2022; 42:6823-6834. [PMID: 38377014 PMCID: PMC9463979 DOI: 10.1523/jneurosci.2410-21.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/21/2022] Open
Abstract
Dysregulation of excitatory and inhibitory signaling is commonly observed in major psychiatric disorders, including schizophrenia, depression, and bipolar disorder, and is often targeted by psychological and pharmacological treatment methods. The balance of excitation and inhibition is highly sensitive to severe psychological stress, one of the strongest risk factors for psychiatric disorders. The role of astrocytes in regulating excitatory and inhibitory signaling is now widely recognized; however, the specific involvement of astrocytes in the context of psychiatric disorders with a history of significant stress exposure remains unclear. In this review, we summarize how astrocytes regulate the balance of excitation and inhibition in the context of stress exposure and severe psychopathology, with a focus on the PFC, a brain area highly implicated in psychopathology. We first focus on preclinical models to demonstrate that the duration of stress (particularly acute vs chronic stress) is key to shaping astrocyte function and downstream behavior. We then provide a hypothesis for how astrocytes are involved in stress-associated cortical signaling imbalance, discuss how this directly contributes to phenotypes of psychopathologies, and provide suggestions for future research. We highlight that astrocytes are a key target to understand and treat the dysregulation of cortical signaling associated with stress-related psychiatric disorders.
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Affiliation(s)
- Dominic Kaul
- Illawarra Health and Medical Research Institute, Northfields Ave, Wollongong, 2522, Australia
- Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia
| | - Sibylle G Schwab
- Illawarra Health and Medical Research Institute, Northfields Ave, Wollongong, 2522, Australia
- Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia
| | - Naguib Mechawar
- Douglas Mental Health University Institute, 6875 LaSalle Blvd, Verdun, Quebec H4H 1R3, Canada
| | - Lezanne Ooi
- Illawarra Health and Medical Research Institute, Northfields Ave, Wollongong, 2522, Australia
- Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia
| | - Natalie Matosin
- Illawarra Health and Medical Research Institute, Northfields Ave, Wollongong, 2522, Australia
- Molecular Horizons, School of Chemistry and Molecular Biosciences, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, Munich, 80804, Germany
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8
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Kwon KM, Pak JH, Jeon CJ. Immunocytochemical localization of the AMPA glutamate receptor subtype GluR2/3 in the squid optic lobe. Acta Histochem 2022; 124:151941. [PMID: 35963117 DOI: 10.1016/j.acthis.2022.151941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/03/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022]
Abstract
As a major excitatory neurotransmitter in the cephalopod visual system, glutamate signaling is facilitated by ionotropic receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR). In cephalopods with large and well-developed brains, the optic lobes (OL) mainly process visual inputs and are involved in learning and memory. Although the presence of AMPAR in squid OL has been reported, the organization of specific AMPAR-containing neurons remains unknown. This study aimed to investigate the immunocytochemical localization of the AMPA glutamate receptor subtype 2/3-immunoreactive (GluR2/3-IR) neurons in the OL of Pacific flying squid (Tordarodes pacificus). Morphologically diverse GluR2/3-IR neurons were predominantly located in the tangential zone of the medulla. Medium-to-large GluR2/3-IR neurons were also detected. The distribution patterns and cell morphologies of calcium-binding protein (CBP)-IR neurons, specifically calbindin-D28K (CB)-, calretinin (CR)-, and parvalbumin (PV)-IR neurons, were similar to those of GluR2/3-IR neurons. However, two-color immunofluorescence revealed that GluR2/3-IR neurons did not colocalize with the CBP-IR neurons. Furthermore, the specific localizations and diverse types of GluR2/3-IR neurons that do not express CB, CR, or PV in squid OL were determined. These findings further contribute to the existing data on glutamatergic visual systems and provide new insights for understanding the visual processing mechanisms in cephalopods.
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Affiliation(s)
- Kyung-Min Kwon
- Department of Biology, School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, College of Natural Sciences, Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Republic of Korea; Research Institute for Dok-do and Ulleung-do Island, Department of Biology, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jae-Hong Pak
- Research Institute for Dok-do and Ulleung-do Island, Department of Biology, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Chang-Jin Jeon
- Department of Biology, School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, College of Natural Sciences, Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Republic of Korea; Research Institute for Dok-do and Ulleung-do Island, Department of Biology, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
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9
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Chen Y, Shen M, Liu X, Xu J, Wang C. The Regulation of Glutamate Transporter 1 in the Rapid Antidepressant-Like Effect of Ketamine in Mice. Front Behav Neurosci 2022; 16:789524. [PMID: 35309681 PMCID: PMC8926310 DOI: 10.3389/fnbeh.2022.789524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Accumulating evidence suggests that glutamate clearance plays a critical role in the pathophysiology and treatment of depression. Preclinical and clinical studies have demonstrated that ketamine provides an immediate and sustained antidepressant effect. However, the precise mechanism of its action remains to be elucidated. Glutamate transporter 1 (GLT1) participates in glutamate clearance; therefore, we hypothesized that GLT1 may play an important role in the antidepressant effect of ketamine. In this study, we determined that GLT1 inhibition blocks the antidepressant-like properties of ketamine and alters the phosphorylation of the mammalian target of rapamycin (mTOR) in the prefrontal cortex (PFC). Our results show that pretreatment with dihydrokainic acid (DHK), a GLT1 inhibitor, alleviated the antidepressant-like effect of ketamine, and decreased the level of phosphorylated mTOR (pmTOR) in mice (which is normally upregulated by ketamine). In addition, inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor and L-type voltage-dependent calcium channel (L-VDCC) significantly abolished the antidepressant-like effect of ketamine. Moreover, inhibition of L-VDCC significantly blocked the upregulation of GLT1 and BDNF in the PFC of mice. The inhibition of the AMPA receptor only significantly alleviated BDNF. Our results provide insight into the role of GLT1 as the critical presynaptic molecule participating in the pathophysiological mechanism of depression and contributing to the antidepressant-like effect of ketamine. In addition, our study confirms that both AMPA receptor and L-VDCC are crucial factors in the immediate antidepressant-like effect of ketamine.
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Affiliation(s)
- Yaping Chen
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Mengxin Shen
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, China
| | - Xu Liu
- Department of Pharmacy, General Hospital of Chinese People’s Armed Police Forces, Beijing, China
| | - Jiangping Xu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
- *Correspondence: Jiangping Xu, , orcid.org/0000-0002-0447-9229
| | - Chuang Wang
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, China
- Chuang Wang, , , orcid.org/0000-0002-3816-230X
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10
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Uchida M, Noda Y, Hasegawa S, Hida H, Taniguchi M, Mouri A, Yoshimi A, Nabeshima T, Yamada K, Aida T, Tanaka K, Ozaki N. Early postnatal inhibition of GLAST causes abnormalities of psychobehaviors and neuronal morphology in adult mice. Neurochem Int 2021; 150:105177. [PMID: 34481039 DOI: 10.1016/j.neuint.2021.105177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/17/2021] [Accepted: 08/31/2021] [Indexed: 11/26/2022]
Abstract
The importance of glutamate transporters in learning, memory, and emotion remains poorly understood; hence, in the present study, we investigated whether deficiency of pharmacological GLAST in neurodevelopmental processes affects cognitive and/or emotional behaviors in mice. The mice were injected with a glutamate transporter inhibitor, dl-threo-β-benzyloxyaspartate (dl-TBOA), during the early postnatal period. At 8 weeks of age, they showed impairments in cognitive or emotional behaviors; dysfunction of glutamatergic neurotransmission (increased expressions of GLAST, GLT-1, or GFAP protein, and decreased ability of glutamate release) in the cortex or hippocampus; morphological changes (decreased cell size in the cortex and thickness of the pyramidal neuronal layer of the CA1 area in the hippocampus). Such behavioral and morphological changes were not observed in adult mice injected with dl-TBOA. These results suggest that GLAST plays an important role in the regulation of cognitive and emotional behaviors. Early postnatal glutamatergic facilitation by GLAST dysfunction leads to cognitive and emotional abnormalities due to neurodevelopmental abnormalities such as morphological changes.
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Affiliation(s)
- Mizuki Uchida
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan
| | - Yukihiro Noda
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan; Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.
| | - Sho Hasegawa
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan
| | - Hirotake Hida
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan; Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Masayuki Taniguchi
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan
| | - Akihiro Mouri
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan
| | - Akira Yoshimi
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Graduate School of Health Sciences, Fujita Health University, Toyoake, Aichi, 470-1192, Japan
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Tomomi Aida
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Kohichi Tanaka
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
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11
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Hickmott RA, Bosakhar A, Quezada S, Barresi M, Walker DW, Ryan AL, Quigley A, Tolcos M. The One-Stop Gyrification Station - Challenges and New Technologies. Prog Neurobiol 2021; 204:102111. [PMID: 34166774 DOI: 10.1016/j.pneurobio.2021.102111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/31/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022]
Abstract
The evolution of the folded cortical surface is an iconic feature of the human brain shared by a subset of mammals and considered pivotal for the emergence of higher-order cognitive functions. While our understanding of the neurodevelopmental processes involved in corticogenesis has greatly advanced over the past 70 years of brain research, the fundamental mechanisms that result in gyrification, along with its originating cytoarchitectural location, remain largely unknown. This review brings together numerous approaches to this basic neurodevelopmental problem, constructing a narrative of how various models, techniques and tools have been applied to the study of gyrification thus far. After a brief discussion of core concepts and challenges within the field, we provide an analysis of the significant discoveries derived from the parallel use of model organisms such as the mouse, ferret, sheep and non-human primates, particularly with regard to how they have shaped our understanding of cortical folding. We then focus on the latest developments in the field and the complementary application of newly emerging technologies, such as cerebral organoids, advanced neuroimaging techniques, and atomic force microscopy. Particular emphasis is placed upon the use of novel computational and physical models in regard to the interplay of biological and physical forces in cortical folding.
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Affiliation(s)
- Ryan A Hickmott
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia; BioFab3D@ACMD, St Vincent's Hospital Melbourne, Fitzroy, VIC, 3065, Australia
| | - Abdulhameed Bosakhar
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia
| | - Sebastian Quezada
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia
| | - Mikaela Barresi
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia
| | - David W Walker
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia
| | - Amy L Ryan
- Hastings Centre for Pulmonary Research, Department of Pulmonary, Critical Care and Sleep Medicine, USC Keck School of Medicine, University of Southern California, CA, USA and Department of Stem Cell and Regenerative Medicine, University of Southern California, CA, 90033, USA
| | - Anita Quigley
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia; BioFab3D@ACMD, St Vincent's Hospital Melbourne, Fitzroy, VIC, 3065, Australia; School of Engineering, RMIT University, Melbourne, VIC, 3000, Australia; Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, VIC, 3065, Australia; ARC Centre of Excellence in Electromaterials Science, University of Wollongong, Wollongong, NSW, 2522, Australia
| | - Mary Tolcos
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia.
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12
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Rodríguez-Campuzano AG, Ortega A. Glutamate transporters: Critical components of glutamatergic transmission. Neuropharmacology 2021; 192:108602. [PMID: 33991564 DOI: 10.1016/j.neuropharm.2021.108602] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/09/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023]
Abstract
Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. Once released, it binds to specific membrane receptors and transporters activating a wide variety of signal transduction cascades, as well as its removal from the synaptic cleft in order to avoid its extracellular accumulation and the overstimulation of extra-synaptic receptors that might result in neuronal death through a process known as excitotoxicity. Although neurodegenerative diseases are heterogenous in clinical phenotypes and genetic etiologies, a fundamental mechanism involved in neuronal degeneration is excitotoxicity. Glutamate homeostasis is critical for brain physiology and Glutamate transporters are key players in maintaining low extracellular Glutamate levels. Therefore, the characterization of Glutamate transporters has been an active area of glutamatergic research for the last 40 years. Transporter activity its regulated at different levels: transcriptional and translational control, transporter protein trafficking and membrane mobility, and through extensive post-translational modifications. The elucidation of these mechanisms has emerged as an important piece to shape our current understanding of glutamate actions in the nervous system.
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Affiliation(s)
- Ada G Rodríguez-Campuzano
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, Ciudad de México, 07000, Mexico
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, Ciudad de México, 07000, Mexico.
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13
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Abstract
Schizophrenia is a severe and clinically heterogenous mental disorder
affecting approximately 1% of the population worldwide. Despite
tremendous achievements in the field of schizophrenia research, its
precise aetiology remains elusive. Besides dysfunctional neuronal
signalling, the pathophysiology of schizophrenia appears to involve
molecular and functional abnormalities in glial cells, including
astrocytes. This article provides a concise overview of the current
evidence supporting altered astrocyte activity in schizophrenia, which
ranges from findings obtained from post-mortem immunohistochemical
analyses, genetic association studies and transcriptomic
investigations, as well as from experimental investigations of
astrocyte functions in animal models. Integrating the existing data
from these research areas strongly suggests that astrocytes have the
capacity to critically affect key neurodevelopmental and homeostatic
processes pertaining to schizophrenia pathogenesis, including
glutamatergic signalling, synaptogenesis, synaptic pruning and
myelination. The further elucidation of astrocytes functions in health
and disease may, therefore, offer new insights into how these glial
cells contribute to abnormal brain development and functioning
underlying this debilitating mental disorder.
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Affiliation(s)
- Tina Notter
- Tina Notter, Institute of
Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich,
Switzerland. Emails: ;
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14
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Sipe GO, Petravicz J, Rikhye RV, Garcia R, Mellios N, Sur M. Astrocyte glutamate uptake coordinates experience-dependent, eye-specific refinement in developing visual cortex. Glia 2021; 69:1723-1735. [PMID: 33675674 DOI: 10.1002/glia.23987] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 12/25/2022]
Abstract
The uptake of glutamate by astrocytes actively shapes synaptic transmission, however its role in the development and plasticity of neuronal circuits remains poorly understood. The astrocytic glutamate transporter, GLT1 is the predominant source of glutamate clearance in the adult mouse cortex. Here, we examined the structural and functional development of the visual cortex in GLT1 heterozygous (HET) mice using two-photon microscopy, immunohistochemistry and slice electrophysiology. We find that though eye-specific thalamic axonal segregation is intact, binocular refinement in the primary visual cortex is disrupted. Eye-specific responses to visual stimuli in GLT1 HET mice show altered binocular matching, with abnormally high responses to ipsilateral compared to contralateral eye stimulation and a greater mismatch between preferred orientation selectivity of ipsilateral and contralateral eye responses. Furthermore, we observe an increase in dendritic spine density in the basal dendrites of layer 2/3 excitatory neurons suggesting aberrant spine pruning. Monocular deprivation induces atypical ocular dominance plasticity in GLT1 HET mice, with an unusual depression of ipsilateral open eye responses; however, this change in ipsilateral responses correlates well with an upregulation of GLT1 protein following monocular deprivation. These results demonstrate that a key function of astrocytic GLT1 function during development is the experience-dependent refinement of ipsilateral eye inputs relative to contralateral eye inputs in visual cortex.
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Affiliation(s)
- Grayson O Sipe
- Department of Brain and Cognitive Sciences, Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Jeremy Petravicz
- Department of Brain and Cognitive Sciences, Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Rajeev V Rikhye
- Department of Brain and Cognitive Sciences, Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Rodrigo Garcia
- Department of Brain and Cognitive Sciences, Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Nikolaos Mellios
- Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.,Autophagy Inflammation and Metabolism (AIM) Center, Albuquerque, New Mexico, USA
| | - Mriganka Sur
- Department of Brain and Cognitive Sciences, Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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15
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Todd AC, Hardingham GE. The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases. Int J Mol Sci 2020; 21:E9607. [PMID: 33348528 PMCID: PMC7766851 DOI: 10.3390/ijms21249607] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 12/04/2020] [Accepted: 12/11/2020] [Indexed: 12/24/2022] Open
Abstract
The astrocytic glutamate transporters excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2) play a key role in nervous system function to maintain extracellular glutamate levels at low levels. In physiology, this is essential for the rapid uptake of synaptically released glutamate, maintaining the temporal fidelity of synaptic transmission. However, EAAT1/2 hypo-expression or hypo-function are implicated in several disorders, including epilepsy and neurodegenerative diseases, as well as being observed naturally with aging. This not only disrupts synaptic information transmission, but in extremis leads to extracellular glutamate accumulation and excitotoxicity. A key facet of EAAT1/2 expression in astrocytes is a requirement for signals from other brain cell types in order to maintain their expression. Recent evidence has shown a prominent role for contact-dependent neuron-to-astrocyte and/or endothelial cell-to-astrocyte Notch signalling for inducing and maintaining the expression of these astrocytic glutamate transporters. The relevance of this non-cell-autonomous dependence to age- and neurodegenerative disease-associated decline in astrocytic EAAT expression is discussed, plus the implications for disease progression and putative therapeutic strategies.
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Affiliation(s)
- Alison C. Todd
- UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK;
- Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
| | - Giles E. Hardingham
- UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK;
- Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
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16
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Felix L, Stephan J, Rose CR. Astrocytes of the early postnatal brain. Eur J Neurosci 2020; 54:5649-5672. [PMID: 32406559 DOI: 10.1111/ejn.14780] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/30/2020] [Accepted: 05/06/2020] [Indexed: 12/21/2022]
Abstract
In the rodent forebrain, the majority of astrocytes are generated during the early postnatal phase. Following differentiation, astrocytes undergo maturation which accompanies the development of the neuronal network. Neonate astrocytes exhibit a distinct morphology and domain size which differs to their mature counterparts. Moreover, many of the plasma membrane proteins prototypical for fully developed astrocytes are only expressed at low levels at neonatal stages. These include connexins and Kir4.1, which define the low membrane resistance and highly negative membrane potential of mature astrocytes. Newborn astrocytes moreover express only low amounts of GLT-1, a glutamate transporter critical later in development. Furthermore, they show specific differences in the properties and spatio-temporal pattern of intracellular calcium signals, resulting from differences in their repertoire of receptors and signalling pathways. Therefore, roles fulfilled by mature astrocytes, including ion and transmitter homeostasis, are underdeveloped in the young brain. Similarly, astrocytic ion signalling in response to neuronal activity, a process central to neuron-glia interaction, differs between the neonate and mature brain. This review describes the unique functional properties of astrocytes in the first weeks after birth and compares them to later stages of development. We conclude that with an immature neuronal network and wider extracellular space, astrocytic support might not be as demanding and critical compared to the mature brain. The delayed differentiation and maturation of astrocytes in the first postnatal weeks might thus reflect a reduced need for active, energy-consuming regulation of the extracellular space and a less tight control of glial feedback onto synaptic transmission.
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Affiliation(s)
- Lisa Felix
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Jonathan Stephan
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Christine R Rose
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
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17
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Arundic acid administration protects astrocytes, recovers histological damage and memory deficits induced by neonatal hypoxia ischemia in rats. Int J Dev Neurosci 2019; 76:41-51. [DOI: 10.1016/j.ijdevneu.2019.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 05/16/2019] [Accepted: 06/12/2019] [Indexed: 11/17/2022] Open
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18
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Ma NX, Yin JC, Chen G. Transcriptome Analysis of Small Molecule-Mediated Astrocyte-to-Neuron Reprogramming. Front Cell Dev Biol 2019; 7:82. [PMID: 31231645 PMCID: PMC6558402 DOI: 10.3389/fcell.2019.00082] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 05/01/2019] [Indexed: 12/21/2022] Open
Abstract
Chemical reprogramming of astrocytes into neurons represents a promising approach to regenerate new neurons for brain repair, but the underlying mechanisms driving this trans-differentiation process are not well understood. We have recently identified four small molecules – CHIR99021, DAPT, LDN193189, and SB431542 – that can efficiently reprogram cultured human fetal astrocytes into functional neurons. Here we employ the next generation of RNA-sequencing technology to investigate the transcriptome changes during the astrocyte-to-neuron (AtN) conversion process. We found that the four small molecules can rapidly activate the hedgehog signaling pathway while downregulating many glial genes such as FN1 and MYL9 within 24 h of treatment. Chemical reprogramming is mediated by several waves of differential gene expression, including upregulation of hedgehog, Wnt/β-catenin, and Notch signaling pathways, together with downregulation of TGF-β and JAK/STAT signaling pathways. Our gene network analyses reveal many well-connected hub genes such as repulsive guidance molecule A (RGMA), neuronatin (NNAT), neurogenin 2 (NEUROG2), NPTX2, MOXD1, JAG1, and GAP43, which may coordinate the chemical reprogramming process. Together, these findings provide critical insights into the molecular cascades triggered by a combination of small molecules that eventually leads to chemical conversion of astrocytes into neurons.
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Affiliation(s)
- Ning-Xin Ma
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA, United States
| | - Jiu-Chao Yin
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA, United States
| | - Gong Chen
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA, United States
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19
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Clifton NE, Trent S, Thomas KL, Hall J. Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity. MOLECULAR NEUROPSYCHIATRY 2019; 5:147-161. [PMID: 31312636 DOI: 10.1159/000500267] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/09/2019] [Indexed: 12/22/2022]
Abstract
Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms. The expression of Homer1a and Ania-3 initiates critical processes of PSD remodeling, the modulation of glutamate receptor-mediated functions, and the regulation of calcium signaling. Together, available data support the view that Homer1a and Ania-3 are responsible for the selective, transient destabilization of postsynaptic signaling complexes to facilitate plasticity of the excitatory synapse. The interruption of activity-dependent Homer proteins disrupts disease-relevant processes and leads to memory impairments, reflecting their likely contribution to neurological disorders.
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Affiliation(s)
- Nicholas E Clifton
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.,MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
| | - Simon Trent
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Kerrie L Thomas
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.,School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Jeremy Hall
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.,MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
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20
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Kandasamy P, Gyimesi G, Kanai Y, Hediger MA. Amino acid transporters revisited: New views in health and disease. Trends Biochem Sci 2018; 43:752-789. [PMID: 30177408 DOI: 10.1016/j.tibs.2018.05.003] [Citation(s) in RCA: 303] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 05/23/2018] [Accepted: 05/25/2018] [Indexed: 02/09/2023]
Abstract
Amino acid transporters (AATs) are membrane-bound transport proteins that mediate transfer of amino acids into and out of cells or cellular organelles. AATs have diverse functional roles ranging from neurotransmission to acid-base balance, intracellular energy metabolism, and anabolic and catabolic reactions. In cancer cells and diabetes, dysregulation of AATs leads to metabolic reprogramming, which changes intracellular amino acid levels, contributing to the pathogenesis of cancer, obesity and diabetes. Indeed, the neutral amino acid transporters (NATs) SLC7A5/LAT1 and SLC1A5/ASCT2 are likely involved in several human malignancies. However, a clinical therapy that directly targets AATs has not yet been developed. The purpose of this review is to highlight the structural and functional diversity of AATs, their diverse physiological roles in different tissues and organs, their wide-ranging implications in human diseases and the emerging strategies and tools that will be necessary to target AATs therapeutically.
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Affiliation(s)
- Palanivel Kandasamy
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland
| | - Gergely Gyimesi
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland
| | - Yoshikatsu Kanai
- Division of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Matthias A Hediger
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
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21
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Parkin GM, Udawela M, Gibbons A, Dean B. Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders. World J Psychiatry 2018; 8:51-63. [PMID: 29988908 PMCID: PMC6033743 DOI: 10.5498/wjp.v8.i2.51] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/15/2018] [Accepted: 06/09/2018] [Indexed: 02/05/2023] Open
Abstract
Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the pre-synaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter (EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.
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Affiliation(s)
- Georgia M Parkin
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
- CRC for Mental Health, Carlton VIC 3053, Australia
| | - Madhara Udawela
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
- CRC for Mental Health, Carlton VIC 3053, Australia
| | - Andrew Gibbons
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
| | - Brian Dean
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
- CRC for Mental Health, Carlton VIC 3053, Australia
- Research Centre for Mental Health, the Faculty of Health, Arts and Design, Swinburne University, Hawthorne VIC 3122, Australia
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22
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mGlu5-mediated signalling in developing astrocyte and the pathogenesis of autism spectrum disorders. Curr Opin Neurobiol 2018; 48:139-145. [DOI: 10.1016/j.conb.2017.12.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 12/18/2017] [Accepted: 12/22/2017] [Indexed: 11/24/2022]
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23
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Rose CR, Felix L, Zeug A, Dietrich D, Reiner A, Henneberger C. Astroglial Glutamate Signaling and Uptake in the Hippocampus. Front Mol Neurosci 2018; 10:451. [PMID: 29386994 PMCID: PMC5776105 DOI: 10.3389/fnmol.2017.00451] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/22/2017] [Indexed: 12/22/2022] Open
Abstract
Astrocytes have long been regarded as essentially unexcitable cells that do not contribute to active signaling and information processing in the brain. Contrary to this classical view, it is now firmly established that astrocytes can specifically respond to glutamate released from neurons. Astrocyte glutamate signaling is initiated upon binding of glutamate to ionotropic and/or metabotropic receptors, which can result in calcium signaling, a major form of glial excitability. Release of so-called gliotransmitters like glutamate, ATP and D-serine from astrocytes in response to activation of glutamate receptors has been demonstrated to modulate various aspects of neuronal function in the hippocampus. In addition to receptors, glutamate binds to high-affinity, sodium-dependent transporters, which results in rapid buffering of synaptically-released glutamate, followed by its removal from the synaptic cleft through uptake into astrocytes. The degree to which astrocytes modulate and control extracellular glutamate levels through glutamate transporters depends on their expression levels and on the ionic driving forces that decrease with ongoing activity. Another major determinant of astrocytic control of glutamate levels could be the precise morphological arrangement of fine perisynaptic processes close to synapses, defining the diffusional distance for glutamate, and the spatial proximity of transporters in relation to the synaptic cleft. In this review, we will present an overview of the mechanisms and physiological role of glutamate-induced ion signaling in astrocytes in the hippocampus as mediated by receptors and transporters. Moreover, we will discuss the relevance of astroglial glutamate uptake for extracellular glutamate homeostasis, focusing on how activity-induced dynamic changes of perisynaptic processes could shape synaptic transmission at glutamatergic synapses.
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Affiliation(s)
- Christine R Rose
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Lisa Felix
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Andre Zeug
- Cellular Neurophysiology, Hannover Medical School, Hannover, Germany
| | - Dirk Dietrich
- Department of Neurosurgery, University of Bonn Medical School, Bonn, Germany
| | - Andreas Reiner
- Cellular Neurobiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany
| | - Christian Henneberger
- Institute of Cellular Neurosciences, University of Bonn Medical School, Bonn, Germany.,German Center for Degenerative Diseases (DZNE), Bonn, Germany.,Institute of Neurology, University College London, London, United Kingdom
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24
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Mei YY, Wu DC, Zhou N. Astrocytic Regulation of Glutamate Transmission in Schizophrenia. Front Psychiatry 2018; 9:544. [PMID: 30459650 PMCID: PMC6232167 DOI: 10.3389/fpsyt.2018.00544] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/12/2018] [Indexed: 01/19/2023] Open
Abstract
According to the glutamate hypothesis of schizophrenia, the abnormality of glutamate transmission induced by hypofunction of NMDA receptors (NMDARs) is causally associated with the positive and negative symptoms of schizophrenia. However, the underlying mechanisms responsible for the changes in glutamate transmission in schizophrenia are not fully understood. Astrocytes, the major regulatory glia in the brain, modulate not only glutamate metabolism but also glutamate transmission. Here we review the recent progress in understanding the role of astrocytes in schizophrenia. We focus on the astrocytic mechanisms of (i) glutamate synthesis via the glutamate-glutamine cycle, (ii) glutamate clearance by excitatory amino acid transporters (EAATs), (iii) D-serine release to activate NMDARs, and (iv) glutamatergic target engagement biomarkers. Abnormality in these processes is highly correlated with schizophrenia phenotypes. These findings will shed light upon further investigation of pathogenesis as well as improvement of biomarkers and therapies for schizophrenia.
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Affiliation(s)
- Yu-Ying Mei
- Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Dong Chuan Wu
- Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Ning Zhou
- Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
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25
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Meyer LC, Paisley CE, Mohamed E, Bigbee JW, Kordula T, Richard H, Lutfy K, Sato-Bigbee C. Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes. Glia 2017; 65:2003-2023. [PMID: 28906039 PMCID: PMC5766282 DOI: 10.1002/glia.23210] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 07/03/2017] [Accepted: 08/04/2017] [Indexed: 12/30/2022]
Abstract
Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.
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Affiliation(s)
- Logan C Meyer
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Caitlin E Paisley
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Esraa Mohamed
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - John W Bigbee
- Department of Anatomy and Neurobiology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Tomasz Kordula
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Hope Richard
- Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Kabirullah Lutfy
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California
| | - Carmen Sato-Bigbee
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
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26
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Drugs to Alter Extracellular Concentration of Glutamate: Modulators of Glutamate Uptake Systems. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-1-4939-7228-9_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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27
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Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity. J Neurosci 2017; 37:8830-8844. [PMID: 28821644 DOI: 10.1523/jneurosci.0730-17.2017] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 08/02/2017] [Accepted: 08/09/2017] [Indexed: 01/07/2023] Open
Abstract
Glutamate-mediated excitotoxicity induces neuronal death by altering various intracellular signaling pathways and is implicated as a common pathogenic pathway in many neurodegenerative diseases. In the case of motor neuron disease, there is significant evidence to suggest that the overactivation of AMPA receptors due to deficiencies in the expression and function of glial glutamate transporters GLT1 and GLAST plays an important role in the mechanisms of neuronal death. However, a causal role for glial glutamate transporter dysfunction in motor neuron death remains unknown. Here, we developed a new animal model of excitotoxicity by conditionally deleting astroglial glutamate transporters GLT1 and GLAST in the spinal cords of mice (GLAST+/-/GLT1-cKO). GLAST+/-/GLT1-cKO mice (both sexes) exhibited nuclear irregularity and calpain-mediated degradation of nuclear pore complexes (NPCs), which are responsible for nucleocytoplasmic transport. These abnormalities were associated with progressive motor neuron loss, severe paralysis, and shortened lifespan. The nuclear export inhibitor KPT-350 slowed but did not prevent motor neuron death, whereas long-term treatment of the AMPA receptor antagonist perampanel and the calpain inhibitor SNJ-1945 had more persistent beneficial effects. Thus, NPC degradation contributes to AMPA receptor-mediated excitotoxic motor neuronal death, and preventing NPC degradation has robust protective effects. Normalization of NPC function could be a novel therapeutic strategy for neurodegenerative disorders in which AMPA receptor-mediated excitotoxicity is a contributory factor.SIGNIFICANCE STATEMENT Despite glial glutamate transporter dysfunction leading to excitotoxicity has been documented in many neurological diseases, it remains unclear whether its dysfunction is a primary cause or secondary outcome of neuronal death at disease state. Here we show the combined loss of glial glutamate transporters GLT1 and GLAST in spinal cord caused motor neuronal death and hindlimb paralysis. Further, our novel mutant exhibits the nuclear irregularities and calpain-mediated progressive nuclear pore complex degradation. Our study reveals that glial glutamate transporter dysfunction is sufficient to cause motor neuronal death in vivo.
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28
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Jiang NW, Wang DJ, Xie YJ, Zhou L, Su LD, Li H, Wang QW, Shen Y. Downregulation of Glutamate Transporter EAAT4 by Conditional Knockout of Rheb1 in Cerebellar Purkinje Cells. THE CEREBELLUM 2017; 15:314-21. [PMID: 26194056 DOI: 10.1007/s12311-015-0701-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Excitatory amino acid transporter 4 (EAAT4) is believed to be critical to the synaptic activity of cerebellar Purkinje cells by limiting extracellular glutamate concentrations and facilitating the induction of long-term depression. However, the modulation of EAAT4 expression has not been elucidated. It has been shown that Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling plays essential roles in the regulation of protein translation, cell size, and cell growth. In addition, we previously found that a cascade including mTOR suppression and Akt activation induces increased expression of EAAT2 in astrocytes. In the present work, we explored whether Rheb/mTOR signaling is involved in the regulation of EAAT4 expression using conditional Rheb1 knockout mice. Our results demonstrated that Rheb1 deficiency resulted in the downregulation of EAAT4 expression, as well as decreased activity of mTOR and increased activity of Akt. The downregulation of EAAT4 was also confirmed by reduced EAAT4 currents and slowed kinetics of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor-mediated currents. On the other hand, conditional knockout of Rheb1 did not alter the morphology of Purkinje cell layer and the number of Purkinje cells. Overall, our findings suggest that small GTPase Rheb1 is a modulator in the expression of EAAT4 in Purkinje cells.
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Affiliation(s)
- Nan-Wei Jiang
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo, 315211, China
| | - De-Juan Wang
- Department of Neurobiology, Zhejiang University School of Medicine, 866 Yu Hang Tang Road, Hangzhou, 310058, China
| | - Ya-Jun Xie
- Department of Neurobiology, Zhejiang University School of Medicine, 866 Yu Hang Tang Road, Hangzhou, 310058, China
| | - Liang Zhou
- Department of Neurobiology, Zhejiang University School of Medicine, 866 Yu Hang Tang Road, Hangzhou, 310058, China
| | - Li-Da Su
- Department of Neurobiology, Zhejiang University School of Medicine, 866 Yu Hang Tang Road, Hangzhou, 310058, China.,Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Huashun Li
- Shenzhen Key laboratory for Molecular Biology of Neural Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Qin-Wen Wang
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo, 315211, China.
| | - Ying Shen
- Department of Neurobiology, Zhejiang University School of Medicine, 866 Yu Hang Tang Road, Hangzhou, 310058, China.
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29
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Murphy-Royal C, Dupuis J, Groc L, Oliet SHR. Astroglial glutamate transporters in the brain: Regulating neurotransmitter homeostasis and synaptic transmission. J Neurosci Res 2017; 95:2140-2151. [PMID: 28150867 DOI: 10.1002/jnr.24029] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 12/20/2016] [Accepted: 01/02/2017] [Indexed: 12/29/2022]
Abstract
Astrocytes, the major glial cell type in the central nervous system (CNS), are critical for brain function and have been implicated in various disorders of the central nervous system. These cells are involved in a wide range of cerebral processes including brain metabolism, control of central blood flow, ionic homeostasis, fine-tuning synaptic transmission, and neurotransmitter clearance. Such varied roles can be efficiently carried out due to the intimate interactions astrocytes maintain with neurons, the vasculature, as well as with other glial cells. Arguably, one of the most important functions of astrocytes in the brain is their control of neurotransmitter clearance. This is particularly true for glutamate whose timecourse in the synaptic cleft needs to be controlled tightly under physiological conditions to maintain point-to-point excitatory transmission, thereby limiting spillover and activation of more receptors. Most importantly, accumulation of glutamate in the extracellular space can trigger excessive activation of glutamatergic receptors and lead to excitotoxicity, a trademark of many neurodegenerative diseases. It is thus of utmost importance for both physiological and pathophysiological reasons to understand the processes that control glutamate time course within the synaptic cleft and regulate its concentrations in the extracellular space. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Ciaran Murphy-Royal
- Neurocentre Magendie, Inserm U1215, Bordeaux, France.,Université de Bordeaux, Bordeaux, France
| | - Julien Dupuis
- Université de Bordeaux, Bordeaux, France.,Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Bordeaux, France
| | - Laurent Groc
- Université de Bordeaux, Bordeaux, France.,Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Bordeaux, France
| | - Stéphane H R Oliet
- Neurocentre Magendie, Inserm U1215, Bordeaux, France.,Université de Bordeaux, Bordeaux, France
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30
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Rose CR, Ziemens D, Untiet V, Fahlke C. Molecular and cellular physiology of sodium-dependent glutamate transporters. Brain Res Bull 2016; 136:3-16. [PMID: 28040508 DOI: 10.1016/j.brainresbull.2016.12.013] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 02/04/2023]
Abstract
Glutamate is the major excitatory transmitter in the vertebrate brain. After its release from presynaptic nerve terminals, it is rapidly taken up by high-affinity sodium-dependent plasma membrane transporters. While both neurons and glial cells express these excitatory amino acid transporters (EAATs), the majority of glutamate uptake is accomplished by astrocytes, which convert synaptically-released glutamate to glutamine or feed it into their own metabolism. Glutamate uptake by astrocytes not only shapes synaptic transmission by regulating the availability of glutamate to postsynaptic neuronal receptors, but also protects neurons from hyper-excitability and subsequent excitotoxic damage. In the present review, we provide an overview of the molecular and cellular characteristics of sodium-dependent glutamate transporters and their associated anion permeation pathways, with a focus on astrocytic glutamate transport. We summarize their functional properties and roles within tripartite synapses under physiological and pathophysiological conditions, exemplifying the intricate interactions and interrelationships between neurons and glial cells in the brain.
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Affiliation(s)
- Christine R Rose
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany.
| | - Daniel Ziemens
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Verena Untiet
- Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, Germany
| | - Christoph Fahlke
- Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, Germany
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31
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Danbolt NC, Furness DN, Zhou Y. Neuronal vs glial glutamate uptake: Resolving the conundrum. Neurochem Int 2016; 98:29-45. [PMID: 27235987 DOI: 10.1016/j.neuint.2016.05.009] [Citation(s) in RCA: 158] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 05/03/2016] [Accepted: 05/17/2016] [Indexed: 12/30/2022]
Abstract
Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.
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Affiliation(s)
- N C Danbolt
- The Neurotransporter Group, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
| | - D N Furness
- School of Life Sciences, Keele University, Keele, Staffs. ST5 5BG, UK
| | - Y Zhou
- The Neurotransporter Group, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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32
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Chrobak AA, Soltys Z. Bergmann Glia, Long-Term Depression, and Autism Spectrum Disorder. Mol Neurobiol 2016; 54:1156-1166. [PMID: 26809583 PMCID: PMC5310553 DOI: 10.1007/s12035-016-9719-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 01/12/2016] [Indexed: 12/22/2022]
Abstract
Bergmann glia (BG), a specific type of radial astrocytes in the cerebellum, play a variety of vital functions in the development of this structure. However, the possible role of BG in the development of abnormalities observed in individuals with autism spectrum disorder (ASD) seems to be underestimated. One of the most consistent findings observed in ASD patients is loss of Purkinje cells (PCs). Such a defect may be caused by dysregulation of glutamate homeostasis, which is maintained mainly by BG. Moreover, these glial cells are involved in long-term depression (LTD), a form of plasticity which can additionally subserve neuroprotective functions. The aim of presented review is to summarize the current knowledge about interactions which occur between PC and BG, with special emphasis on those which are relevant to the survival and proper functioning of cerebellar neurons.
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Affiliation(s)
- Adrian Andrzej Chrobak
- Department of Neuroanatomy, Institute of Zoology, Jagiellonian University, Gronostajowa St. 9, Cracow, 30-387, Poland. .,Faculty of Medicine, Jagiellonian University Medical College, Kopernika St. 21A, Cracow, 31-501, Poland.
| | - Zbigniew Soltys
- Department of Neuroanatomy, Institute of Zoology, Jagiellonian University, Gronostajowa St. 9, Cracow, 30-387, Poland
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33
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Melendez RI, Roman C, Capo-Velez CM, Lasalde-Dominicci JA. Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J Neurovirol 2015; 22:358-65. [PMID: 26567011 DOI: 10.1007/s13365-015-0403-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 10/27/2015] [Accepted: 10/30/2015] [Indexed: 12/22/2022]
Abstract
The mechanisms leading to the neurocognitive deficits in humans with immunodeficiency virus type 1 (HIV-1) are not well resolved. A number of cell culture models have demonstrated that the HIV-envelope glycoprotein 120 (gp120) decreases the reuptake of glutamate, which is necessary for learning, memory, and synaptic plasticity. However, the impact of brain HIV-1 gp120 on glutamate uptake systems in vivo remains unknown. Notably, alterations in brain glutamate uptake systems are implicated in a number of neurodegenerative and neurocognitive disorders. We characterized the kinetic properties of system XAG (sodium-dependent) and systems xc- (sodium-independent) [3H]-L-glutamate uptake in the striatum and hippocampus of HIV-1 gp120 transgenic mice, an established model of HIV neuropathology. We determined the kinetic constant Vmax (maximal velocity) and Km (affinity) of both systems XAG and xc- using subcellular preparations derived from neurons and glial cells. We show significant (30-35 %) reductions in the Vmax of systems XAG and xc- in both neuronal and glial preparations derived from the striatum, but not from the hippocampus of gp120 mice relative to wild-type (WT) controls. Moreover, immunoblot analysis showed that the protein expression of glutamate transporter subtype-1 (GLT-1), the predominant brain glutamate transporter, was significantly reduced in the striatum but not in the hippocampus of gp120 mice. These extensive and region-specific deficits of glutamate uptake likely contribute to the development and/or severity of HIV-associated neurocognitive disorders. Understanding the role of striatal glutamate uptake systems in HIV-1 gp120 may advance the development of new therapeutic strategies to prevent neuronal damage and improve cognitive function in HIV patients.
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Affiliation(s)
- Roberto I Melendez
- Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, Office #A-527, San Juan, 00936, Puerto Rico.
| | - Cristina Roman
- Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, Office #A-527, San Juan, 00936, Puerto Rico
| | - Coral M Capo-Velez
- Department of Biology, University of Puerto Rico, Rio Piedras, PR, 00936, USA
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34
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Fontana ACK. Current approaches to enhance glutamate transporter function and expression. J Neurochem 2015; 134:982-1007. [DOI: 10.1111/jnc.13200] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 05/19/2015] [Accepted: 05/20/2015] [Indexed: 12/12/2022]
Affiliation(s)
- Andréia C. K. Fontana
- Department of Pharmacology and Physiology; Drexel University College of Medicine; Philadelphia Pennsylvania USA
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35
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Aida T, Yoshida J, Nomura M, Tanimura A, Iino Y, Soma M, Bai N, Ito Y, Cui W, Aizawa H, Yanagisawa M, Nagai T, Takata N, Tanaka KF, Takayanagi R, Kano M, Götz M, Hirase H, Tanaka K. Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice. Neuropsychopharmacology 2015; 40:1569-79. [PMID: 25662838 PMCID: PMC4915262 DOI: 10.1038/npp.2015.26] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 01/10/2015] [Accepted: 01/10/2015] [Indexed: 02/04/2023]
Abstract
An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLAST(CreERT2/+)/GLT1(flox/flox), iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.
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Affiliation(s)
- Tomomi Aida
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Junichi Yoshida
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masatoshi Nomura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Asami Tanimura
- Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yusuke Iino
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miho Soma
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ning Bai
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yukiko Ito
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Wanpeng Cui
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hidenori Aizawa
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Michiko Yanagisawa
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Terumi Nagai
- Laboratory for Neuron-Glia Circuitry, Brain Science Institute, RIKEN, Saitama, Japan
| | - Norio Takata
- Laboratory for Neuron-Glia Circuitry, Brain Science Institute, RIKEN, Saitama, Japan
| | - Kenji F Tanaka
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masanobu Kano
- Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Magdalena Götz
- Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Munich, Germany
| | - Hajime Hirase
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Kohichi Tanaka
- Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan,JST, CREST, Saitama, Japan,The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan,Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-Ku, Tokyo 113-8510, Japan, Tel: +81 3 5803 5846, Fax: +81 3 5803 5843, E-mail:
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36
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Šerý O, Sultana N, Kashem MA, Pow DV, Balcar VJ. GLAST But Not Least--Distribution, Function, Genetics and Epigenetics of L-Glutamate Transport in Brain--Focus on GLAST/EAAT1. Neurochem Res 2015; 40:2461-72. [PMID: 25972039 DOI: 10.1007/s11064-015-1605-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 04/30/2015] [Accepted: 05/05/2015] [Indexed: 12/12/2022]
Abstract
Synaptically released L-glutamate, the most important excitatory neurotransmitter in the CNS, is removed from extracellular space by fast and efficient transport mediated by several transporters; the most abundant ones are EAAT1/GLAST and EAAT2/GLT1. The review first summarizes their location, functions and basic characteristics. We then look at genetics and epigenetics of EAAT1/GLAST and EAAT2/GLT1 and perform in silico analyses of their promoter regions. There is one CpG island in SLC1A2 (EAAT2/GLT1) gene and none in SLC1A3 (EAAT1/GLAST) suggesting that DNA methylation is not the most important epigenetic mechanism regulating EAAT1/GLAST levels in brain. There are targets for specific miRNA in SLC1A2 (EAAT2/GLT1) gene. We also note that while defects in EAAT2/GLT1 have been associated with various pathological states including chronic neurodegenerative diseases, very little is known on possible contributions of defective or dysfunctional EAAT1/GLAST to any specific brain disease. Finally, we review evidence of EAAT1/GLAST involvement in mechanisms of brain response to alcoholism and present some preliminary data showing that ethanol, at concentrations which may be reached following heavy drinking, can have an effect on the distribution of EAAT1/GLAST in cultured astrocytes; the effect is blocked by baclofen, a GABA-B receptor agonist and a drug potentially useful in the treatment of alcoholism. We argue that more research effort should be focused on EAAT1/GLAST, particularly in relation to alcoholism and drug addiction.
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Affiliation(s)
- Omar Šerý
- Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37, Brno, Czech Republic
- Institute of Animal Physiology and Genetics, Academy of Sciences, Veveří 97, 602 00, Brno, Czech Republic
| | - Nilufa Sultana
- Laboratory of Neurochemistry, Bosch Institute and Discipline of Anatomy and Histology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Mohammed Abul Kashem
- Laboratory of Neurochemistry, Bosch Institute and Discipline of Anatomy and Histology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia
| | - David V Pow
- School of Medical Sciences, RMIT University, Bundoora, VIC, 3083, Australia
| | - Vladimir J Balcar
- Laboratory of Neurochemistry, Bosch Institute and Discipline of Anatomy and Histology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia.
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Akanuma SI, Sakurai T, Tachikawa M, Kubo Y, Hosoya KI. Transporter-mediated L-glutamate elimination from cerebrospinal fluid: possible involvement of excitatory amino acid transporters expressed in ependymal cells and choroid plexus epithelial cells. Fluids Barriers CNS 2015; 12:11. [PMID: 25925580 PMCID: PMC4425921 DOI: 10.1186/s12987-015-0006-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 04/11/2015] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND L-Glutamate (L-Glu) is the major excitatory neurotransmitter in the CNS, and its level in cerebrospinal fluid (CSF) is reported to be increased in neuroexcitatory diseases such as epilepsy. Since L-Glu concentration in the CSF is reported to be lower than that in plasma, it has been proposed that some mechanisms of L-Glu clearance from the CSF operate in the brain. The purpose of this study was to elucidate the major pathway of L-Glu elimination from rat CSF and the transporters responsible. METHODS Protein expression and localization of excitatory amino acid transporters were examined by immunohistochemical analysis using specific antibodies. In vivo elimination of L-Glu from rat CSF was evaluated by intracerebroventricular administration. An L-Glu uptake study by using primary-cultured rat ependymal cells and isolated rat choroid plexus was performed to characterize L-Glu transport mechanisms. RESULTS An immunohistochemical analysis has shown that excitatory amino acid transporter (EAAT) 1 and EAAT3, which are D-aspartate-sensitive and kainate-insensitive L-Glu transporters, are localized on the CSF-side of rat ependymal cells and choroid plexus epithelial cells, respectively. In contrast, the kainate-sensitive L-Glu transporter, EAAT2, is not expressed in these cells. In vivo L-Glu elimination clearance from the rat CSF (189 μL/(min · rat)) was 23-fold higher than the CSF bulk flow rate, indicating that facilitative process(es) are involved in L-Glu elimination from the CSF. The in vivo [(3)H]L-Glu elimination from the CSF was significantly inhibited by unlabeled L-Glu and D-aspartate, but not kainate. Moreover, unlabeled L-Glu and D-aspartate inhibited [(3)H]L-Glu uptake by rat ependymal cells and choroid plexus epithelial cells, whereas kainate had little effect. CONCLUSION It is suggested that EAAT1 in ependymal cells and EAAT3 in choroid plexus epithelial cells participate in L-Glu elimination from the CSF.
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Affiliation(s)
- Shin-ichi Akanuma
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Tatsuhiko Sakurai
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Masanori Tachikawa
- Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
| | - Yoshiyuki Kubo
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Ken-ichi Hosoya
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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Liu L, Mao D, Liu L, Huang Y, Bo T. Effects of progesterone on glutamate transporter 2 and gamma-aminobutyric acid transporter 1 expression in the developing rat brain after recurrent seizures. Neural Regen Res 2015; 7:2036-42. [PMID: 25624835 PMCID: PMC4296423 DOI: 10.3969/j.issn.1673-5374.2012.26.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2012] [Accepted: 06/15/2012] [Indexed: 12/21/2022] Open
Abstract
Seizures were induced by flurothyl inhalation. Rats were intramuscularly treated with progesterone after each seizure. Results demonstrated that glutamate transporter 2 and γ-aminobutyric acid transporter 1 expression levels were significantly increased in the cerebral cortex and hippocampus of the developing rat brain following recurrent seizures. After progesterone treatment, glutamate transporter 2 protein expression was upregulated, but γ-aminobutyric acid transporter 1 levels decreased. These results suggest that glutamate transporter 2 and γ-aminobutyric acid transporter 1 are involved in the pathological processes of epilepsy. Progesterone can help maintain a balance between excitatory and inhibitory systems by modulating the amino acid transporter system, and protect the developing brain after recurrent seizures.
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Affiliation(s)
- Lingjuan Liu
- Department of Pediatrics, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Dingan Mao
- Department of Pediatrics, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Liqun Liu
- Department of Pediatrics, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Yu Huang
- Department of Pediatrics, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Tao Bo
- Department of Pediatrics, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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Busanello ENB, Fernandes CG, Martell RV, Lobato VGA, Goodman S, Woontner M, de Souza DOG, Wajner M. Disturbance of the glutamatergic system by glutaric acid in striatum and cerebral cortex of glutaryl-CoA dehydrogenase-deficient knockout mice: Possible implications for the neuropathology of glutaric acidemia type I. J Neurol Sci 2014; 346:260-7. [DOI: 10.1016/j.jns.2014.09.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 08/21/2014] [Accepted: 09/03/2014] [Indexed: 11/30/2022]
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GLT-1 transporter: an effective pharmacological target for various neurological disorders. Pharmacol Biochem Behav 2014; 127:70-81. [PMID: 25312503 DOI: 10.1016/j.pbb.2014.10.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 09/01/2014] [Accepted: 10/03/2014] [Indexed: 11/23/2022]
Abstract
L-Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS) and is directly and indirectly involved in a variety of brain functions. Glutamate is released in the synaptic cleft at a particular concentration that further activates the various glutaminergic receptors. This concentration of glutamate in the synapse is maintained by either glutamine synthetase or excitatory amino acid proteins which reuptake the excessive glutamate from the synapse and named as excitatory amino acid transporters (EAATs). Out of all the subtypes GLT-1 (glutamate transporter 1) is abundantly distributed in the CNS. Down-regulation of GLT-1 is reported in various neurological diseases such as, epilepsy, stroke, Alzheimer's disease and movement disorders. Therefore, positive modulators of GLT-1 which up-regulate the GLT-1 expression can serve as a potential target for the treatment of neurological disorders. GLT-1 translational activators such as ceftriaxone are found to have significant protective effects in ALS and epilepsy animal models, suggesting that this translational activation approach works well in rodents and that these compounds are worth further pursuit for various neurological disorders. This drug is currently in human clinical trials for ALS. In addition, a thorough understanding of the mechanisms underlying translational regulation of GLT-1, such as identifying the molecular targets of the compounds, signaling pathways involved in the regulation, and translational activation processes, is very important for this novel drug-development effort. This review mainly emphasizes the role of glutamate and its transporter, GLT-1 subtype in excitotoxicity. Further, recent reports on GLT-1 transporters for the treatment of various neurological diseases, including a summary of the presumed physiologic mechanisms behind the pharmacology of these disorders are also explained.
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Martinez-Lozada Z, Waggener CT, Kim K, Zou S, Knapp PE, Hayashi Y, Ortega A, Fuss B. Activation of sodium-dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin-dependent kinase IIβ's actin-binding/-stabilizing domain. Glia 2014; 62:1543-1558. [PMID: 24866099 PMCID: PMC4107011 DOI: 10.1002/glia.22699] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 05/08/2014] [Accepted: 05/09/2014] [Indexed: 02/06/2023]
Abstract
Signaling via the major excitatory amino acid glutamate has been implicated in the regulation of various aspects of the biology of oligodendrocytes, the myelinating cells of the central nervous system (CNS). In this respect, cells of the oligodendrocyte lineage have been described to express a variety of glutamate-responsive transmembrane proteins including sodium-dependent glutamate transporters. The latter have been well characterized to mediate glutamate clearance from the extracellular space. However, there is increasing evidence that they also mediate glutamate-induced intracellular signaling events. Our data presented here show that the activation of oligodendrocyte expressed sodium-dependent glutamate transporters, in particular GLT-1 and GLAST, promotes the morphological aspects of oligodendrocyte maturation. This effect was found to be associated with a transient increase in intracellular calcium levels and a transient phosphorylation event at the serine (S)(371) site of the calcium sensor calcium/calmodulin-dependent kinase type IIβ (CaMKIIβ). The potential regulatory S(371) site is located within CaMKIIβ's previously defined actin-binding/-stabilizing domain, and phosphorylation events within this domain were identified in our studies as a requirement for sodium-dependent glutamate transporter-mediated promotion of oligodendrocyte maturation. Furthermore, our data provide good evidence for a role of these phosphorylation events in mediating detachment of CaMKIIβ from filamentous (F)-actin, and hence allowing a remodeling of the oligodendrocyte's actin cytoskeleton. Taken together with our recent findings, which demonstrated a crucial role of CaMKIIβ in regulating CNS myelination in vivo, our data strongly suggest that a sodium-dependent glutamate transporter-CaMKIIβ-actin cytoskeleton axis plays an important role in the regulation of oligodendrocyte maturation and CNS myelination.
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Affiliation(s)
- Zila Martinez-Lozada
- Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F, México
| | - Christopher T. Waggener
- Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA
| | - Karam Kim
- Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan
| | - Shiping Zou
- Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA
| | - Pamela E. Knapp
- Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA
| | - Yasunori Hayashi
- Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan
- Saitama University Brain Science Institute, Saitama University, Saitama 338-8570, Japan
| | - Arturo Ortega
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F, México
| | - Babette Fuss
- Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA
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Schreiner AE, Durry S, Aida T, Stock MC, Rüther U, Tanaka K, Rose CR, Kafitz KW. Laminar and subcellular heterogeneity of GLAST and GLT-1 immunoreactivity in the developing postnatal mouse hippocampus. J Comp Neurol 2014; 522:204-24. [PMID: 23939750 DOI: 10.1002/cne.23450] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 05/23/2013] [Accepted: 08/02/2013] [Indexed: 11/06/2022]
Abstract
Astrocytes express two sodium-coupled transporters, glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), which are essential for the maintenance of low extracellular glutamate levels. We performed a comparative analysis of the laminar and subcellular expression profile of GLAST and GLT-1 in the developing postnatal mouse hippocampus by using immunohistochemistry and western blotting and employing high-resolution fluorescence microscopy. Astrocytes were identified by costaining with glial fibrillary acidic protein (GFAP) or S100β. In CA1, the density of GFAP-positive cells and GFAP expression rose during the first 2 weeks after birth, paralleled by a steady increase in GLAST immunoreactivity and protein content. Upregulation of GLT-1 was completed only at postnatal days (P) P20-25 and was thus delayed by about 10 days. GLAST staining was highest along the stratum pyramidale and was especially prominent in astrocytes at P3-5. GLAST immunoreactivity indicated no preferential localization to a specific cellular compartment. GLT-1 exhibited a laminar expression pattern from P10-15 on, with the highest immunoreactivity in the stratum lacunosum-moleculare. At the cellular level, GLT-1 immunoreactivity did not entirely cover astrocyte somata and exhibited clusters at processes. In neonatal and juvenile animals, discrete clusters of GLT-1 were also detected at perivascular endfeet. From these results, we conclude there is a remarkable subcellular heterogeneity of GLAST and GLT-1 expression in the developing hippocampus. The clustering of GLT-1 at astrocyte endfeet indicates that it might serve a specialized functional role at the blood-brain barrier during formation of the hippocampal network.
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Affiliation(s)
- Alexandra E Schreiner
- Institute of Neurobiology, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany
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Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna) 2014; 121:799-817. [PMID: 24578174 PMCID: PMC4133642 DOI: 10.1007/s00702-014-1180-8] [Citation(s) in RCA: 585] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 02/11/2014] [Indexed: 12/13/2022]
Abstract
Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways. Considering this, it was a surprise to discover that glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as "excitotoxicity". This effect is due to glutamate receptors present on the surface of brain cells. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. Further, the blood-brain barrier shields the brain from glutamate in the blood. The highest concentrations of glutamate are found in synaptic vesicles in nerve terminals from where it can be released by exocytosis. In fact, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It took, however, a long time to realize that. The present review provides a brief historical description, gives a short overview of glutamate as a transmitter in the healthy brain, and comments on the so-called glutamate-glutamine cycle. The glutamate transporters responsible for the glutamate removal are described in some detail.
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Affiliation(s)
- Y. Zhou
- The Neurotransporter Group, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, P.O. Box 1105, 0317 Oslo, Norway
| | - N. C. Danbolt
- The Neurotransporter Group, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, P.O. Box 1105, 0317 Oslo, Norway
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Lecointre M, Hauchecorne M, Chaussivert A, Marret S, Leroux P, Jegou S, Leroux-Nicollet I, Gonzalez BJ, Henry VJ. The efficiency of glutamate uptake differs between neonatal and adult cortical microvascular endothelial cells. J Cereb Blood Flow Metab 2014; 34:764-7. [PMID: 24517976 PMCID: PMC4013767 DOI: 10.1038/jcbfm.2014.30] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/27/2013] [Accepted: 01/19/2014] [Indexed: 11/09/2022]
Abstract
Glutamate transporters (excitatory amino-acid transporters (EAATs)) are essential for brain homeostasis. While previous studies indicate that the vascular endothelium contributes to glutamate efflux in the adult brain, little information is available regarding glutamate uptake in the immature brain. The present study shows a differential expression pattern of EAATs between cortical microvessels in adults and newborns. In addition, adult cortical endothelial cells take up glutamate more efficiently than neonatal cells. Our findings indicate age-specific changes in extracellular glutamate regulation by brain endothelial cells, suggesting differences in the efficiency of glutamate efflux during an excitotoxic process that, in turn, may contribute to age-specific brain vulnerability.
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Affiliation(s)
- Maryline Lecointre
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Michelle Hauchecorne
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Armelle Chaussivert
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Stéphane Marret
- 1] ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France [2] Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital, Rouen, France
| | - Philippe Leroux
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Sylvie Jegou
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Isabelle Leroux-Nicollet
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Bruno J Gonzalez
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
| | - Vincent J Henry
- ERI28 NeoVasc, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France
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Wang X, Patel ND, Hui D, Pal R, Hafez MM, Sayed-Ahmed MM, Al-Yahya AA, Michaelis EK. Gene expression patterns in the hippocampus during the development and aging of Glud1 (Glutamate Dehydrogenase 1) transgenic and wild type mice. BMC Neurosci 2014; 15:37. [PMID: 24593767 PMCID: PMC3973933 DOI: 10.1186/1471-2202-15-37] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 02/24/2014] [Indexed: 11/22/2022] Open
Abstract
Background Extraneuronal levels of the neurotransmitter glutamate in brain rise during aging. This is thought to lead to synaptic dysfunction and neuronal injury or death. To study the effects of glutamate hyperactivity in brain, we created transgenic (Tg) mice in which the gene for glutamate dehydrogenase (Glud1) is over-expressed in neurons and in which such overexpression leads to excess synaptic release of glutamate. In this study, we analyzed whole genome expression in the hippocampus, a region important for learning and memory, of 10 day to 20 month old Glud1 and wild type (wt) mice. Results During development, maturation and aging, both Tg and wt exhibited decreases in the expression of genes related to neurogenesis, neuronal migration, growth, and process elongation, and increases in genes related to neuro-inflammation, voltage-gated channel activity, and regulation of synaptic transmission. Categories of genes that were differentially expressed in Tg vs. wt during development were: synaptic function, cytoskeleton, protein ubiquitination, and mitochondria; and, those differentially expressed during aging were: synaptic function, vesicle transport, calcium signaling, protein kinase activity, cytoskeleton, neuron projection, mitochondria, and protein ubiquitination. Overall, the effects of Glud1 overexpression on the hippocampus transcriptome were greater in the mature and aged than the young. Conclusions Glutamate hyperactivity caused gene expression changes in the hippocampus at all ages. Some of these changes may result in premature brain aging. The identification of these genomic expression differences is important in understanding the effects of glutamate dysregulation on neuronal function during aging or in neurodegenerative diseases.
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Affiliation(s)
- Xinkun Wang
- Higuchi Biosciences Center, University of Kansas, 2099 Constant Ave,, Lawrence, KS 66047, USA.
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Choi IY, Lee P, Wang WT, Hui D, Wang X, Brooks WM, Michaelis EK. Metabolism changes during aging in the hippocampus and striatum of glud1 (glutamate dehydrogenase 1) transgenic mice. Neurochem Res 2014; 39:446-55. [PMID: 24442550 DOI: 10.1007/s11064-014-1239-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 01/03/2014] [Accepted: 01/08/2014] [Indexed: 01/31/2023]
Abstract
The decline in neuronal function during aging may result from increases in extracellular glutamate (Glu), Glu-induced neurotoxicity, and altered mitochondrial metabolism. To study metabolic responses to persistently high levels of Glu at synapses during aging, we used transgenic (Tg) mice that over-express the enzyme Glu dehydrogenase (GDH) in brain neurons and release excess Glu in synapses. Mitochondrial GDH is important in amino acid and carbohydrate metabolism and in anaplerotic reactions. We monitored changes in nineteen neurochemicals in the hippocampus and striatum of adult, middle aged, and aged Tg and wild type (wt) mice, in vivo, using proton ((1)H) magnetic resonance spectroscopy. Significant differences between adult Tg and wt were higher Glu, N-acetyl aspartate (NAA), and NAA + NAA-Glu (NAAG) levels, and lower lactate in the Tg hippocampus and striatum than those of wt. During aging, consistent changes in Tg and wt hippocampus and striatum included increases in myo-inositol and NAAG. The levels of glutamine (Gln), a key neurochemical in the Gln-Glu cycle between neurons and astroglia, increased during aging in both the striatum and hippocampus of Tg mice, but only in the striatum of the wt mice. Age-related increases of Glu were observed only in the striatum of the Tg mice.
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Affiliation(s)
- In-Young Choi
- Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, KS, USA
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Tanaka K. [Role of glutamate transporters in the pathophysiology of major mental illnesses]. Nihon Yakurigaku Zasshi 2013; 142:291-6. [PMID: 24334928 DOI: 10.1254/fpj.142.291] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Aida T, Imahashi R, Tanaka K. Translating human genetics into mouse: The impact of ultra-rapidin vivogenome editing. Dev Growth Differ 2013; 56:34-45. [DOI: 10.1111/dgd.12101] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 10/09/2013] [Accepted: 10/10/2013] [Indexed: 12/26/2022]
Affiliation(s)
- Tomomi Aida
- Laboratory of Molecular Neuroscience; Medical Research Institute; Tokyo Medical and Dental University; 1-5-45 Yushima Bunkyo-Ku Tokyo, 113-8510 Japan
| | - Risa Imahashi
- Laboratory of Molecular Neuroscience; Medical Research Institute; Tokyo Medical and Dental University; 1-5-45 Yushima Bunkyo-Ku Tokyo, 113-8510 Japan
| | - Kohichi Tanaka
- Laboratory of Molecular Neuroscience; Medical Research Institute; Tokyo Medical and Dental University; 1-5-45 Yushima Bunkyo-Ku Tokyo, 113-8510 Japan
- The Center for Brain Integration Research; Tokyo Medical and Dental University; 1-5-45 Yushima Bunkyo-Ku Tokyo, 113-8510 Japan
- JST; CREST; 4-1-8 Honcho Kawaguchi-shi Saitama 332-0012 Japan
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Bjørnsen LP, Hadera MG, Zhou Y, Danbolt NC, Sonnewald U. The GLT-1 (EAAT2; slc1a2) glutamate transporter is essential for glutamate homeostasis in the neocortex of the mouse. J Neurochem 2013; 128:641-9. [PMID: 24224925 DOI: 10.1111/jnc.12509] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 10/18/2013] [Accepted: 10/21/2013] [Indexed: 12/24/2022]
Abstract
Glutamate is the major excitatory neurotransmitter, and is inactivated by cellular uptake catalyzed mostly by the glutamate transporter subtypes GLT-1 (EAAT2) and GLAST (EAAT1). Astrocytes express both GLT-1 and GLAST, while axon terminals in the neocortex only express GLT-1. To evaluate the role of GLT-1 in glutamate homeostasis, we injected GLT-1 knockout (KO) mice and wild-type littermates with [1-(13)C]glucose and [1,2-(13)C]acetate 15 min before euthanization. Metabolite levels were analyzed in extracts from neocortex and cerebellum and (13)C labeling in neocortex. Whereas the cerebellum in GLT-1-deficient mice had normal levels of glutamate, glutamine, and (13)C labeling of metabolites, glutamate level was decreased but labeling from [1-(13)C] glucose was unchanged in the neocortex. The contribution from pyruvate carboxylation toward labeling of these metabolites was unchanged. Labeling from [1,2-(13)C] acetate, originating in astrocytes, was decreased in glutamate and glutamine in the neocortex indicating reduced mitochondrial metabolism in astrocytes. The decreased amount of glutamate in the cortex indicates that glutamine transport into neurons is not sufficient to replenish glutamate lost because of neurotransmission and that GLT-1 plays a role in glutamate homeostasis in the cortex. Glutamate is the major excitatory neurotransmitter, and is inactivated by uptake via GLT-1 (EAAT2) and GLAST (EAAT1) transporters, while axon terminals in the neocortex only express GLT-1. To evaluate the role of GLT-1 in glutamate homeostasis, we used [1-(13)C]glucose and [1,2-(13)C]acetate injection and NMR spectroscopy. The results indicate that glutamine transport into neurons is not sufficient to replenish glutamate lost because of neurotransmission and that GLT-1 plays a role in glutamate homeostasis in the neocortex.
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Affiliation(s)
- Lars Petter Bjørnsen
- Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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Unichenko P, Dvorzhak A, Kirischuk S. Transporter-mediated replacement of extracellular glutamate for GABA in the developing murine neocortex. Eur J Neurosci 2013; 38:3580-8. [DOI: 10.1111/ejn.12380] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 08/21/2013] [Accepted: 09/03/2013] [Indexed: 11/29/2022]
Affiliation(s)
- Petr Unichenko
- Institute of Physiology; University Medical Center of the Johannes Gutenberg University Mainz; Duesbergweg 6 55128 Mainz Germany
| | - Anton Dvorzhak
- Department of Experimental Neurology; Cluster of Excellence Neurocure; University Medicine Charitè; Berlin Germany
| | - Sergei Kirischuk
- Institute of Physiology; University Medical Center of the Johannes Gutenberg University Mainz; Duesbergweg 6 55128 Mainz Germany
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