|
1
|
Zhang G, Huang S, Wei M, Wu Y, Wang J. Excitatory Amino Acid Transporters as Therapeutic Targets in the Treatment of Neurological Disorders: Their Roles and Therapeutic Prospects. Neurochem Res 2025; 50:155. [PMID: 40299102 DOI: 10.1007/s11064-025-04400-3] [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: 03/04/2025] [Revised: 04/01/2025] [Accepted: 04/09/2025] [Indexed: 04/30/2025]
Abstract
Excitatory amino acid transporters (EAATs) are pivotal regulators of glutamate homeostasis in the central nervous system and orchestrate synaptic glutamate clearance through transmembrane transport and the glutamine‒glutamate cycle. The five EAAT subtypes (GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4, and EAAT5) exhibit spatiotemporal-specific expression patterns in neurons and glial cells, and their dysfunction is implicated in diverse neurological pathologies, including epilepsy, amyotrophic lateral sclerosis (ALS), schizophrenia, depression, and retinal degeneration. Mechanistic studies revealed that astrocytic GLT-1 deficiency disrupts glutamate clearance in ALS motor neurons, whereas GLAST genetic variants are linked to both epilepsy susceptibility and glaucomatous retinal ganglion cell degeneration. Three major challenges persist in ongoing research: ① subtype-specific regulatory mechanisms remain unclear; ② compensatory functions of transporters vary significantly across disease models; and ③ clinical translation lacks standardized evaluation criteria. The interaction mechanisms and dynamic roles of EAATs in neurological disorders were systematically investigated in this study, and an integrated approach combining single-cell profiling, stem cell-based disease modeling, and drug screening platforms was proposed. These findings lay the groundwork for novel therapeutic strategies targeting glutamate homeostasis.
Collapse
Affiliation(s)
- Guirui Zhang
- Department of Medicine, Guangxi University of Science and Technology, Liuzhou, 545005, China
| | - Shupeng Huang
- Department of Medicine, Guangxi University of Science and Technology, Liuzhou, 545005, China
| | - Mingzhen Wei
- Department of Medicine, Guangxi University of Science and Technology, Liuzhou, 545005, China
| | - Yongmo Wu
- Department of Medicine, Guangxi University of Science and Technology, Liuzhou, 545005, China
| | - Jin Wang
- Department of Medicine, Guangxi University of Science and Technology, Liuzhou, 545005, China.
- Department of Medical Oncology, Liuzhou Workers' Hospital, Liuzhou, 5450054, China.
- The Second Affiliated Hospital of Guangxi, University of Science and Technology, Guangxi Zhuang Autonomous Region, Liuzhou, 5450054, China.
| |
Collapse
|
|
2
|
Ohki CMY, Benazzato C, van der Linden V, França JV, Toledo CM, Machado RRG, Araujo DB, Oliveira DBL, Neris RS, Assunção-Miranda I, de Oliveira Souza IN, Nogueira CO, Leite PEC, van der Linden H, Figueiredo CP, Durigon EL, Clarke JR, Russo FB, Beltrão-Braga PCB. Zika virus infection impairs synaptogenesis, induces neuroinflammation, and could be an environmental risk factor for autism spectrum disorder outcome. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167097. [PMID: 38408544 DOI: 10.1016/j.bbadis.2024.167097] [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: 08/14/2023] [Revised: 02/20/2024] [Accepted: 02/20/2024] [Indexed: 02/28/2024]
Abstract
Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.
Collapse
Affiliation(s)
| | - Cecília Benazzato
- Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Julia V França
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carmen M Toledo
- Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | | | | | - Romulo S Neris
- Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Iranaia Assunção-Miranda
- Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Clara O Nogueira
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paulo Emilio Corrêa Leite
- Clinical Research Unit of the Antonio Pedro Hospital, Federal Fluminense University, Rio de Janeiro, Brazil
| | | | - Claudia P Figueiredo
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Edison Luiz Durigon
- Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Institut Pasteur de São Paulo, São Paulo, Brazil
| | - Julia R Clarke
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | |
Collapse
|
|
3
|
Li Z, Li X, Jin M, Liu Y, He Y, Jia N, Cui X, Liu Y, Hu G, Yu Q. Identification of potential biomarkers and their correlation with immune infiltration cells in schizophrenia using combinative bioinformatics strategy. Psychiatry Res 2022; 314:114658. [PMID: 35660966 DOI: 10.1016/j.psychres.2022.114658] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 05/17/2022] [Accepted: 05/29/2022] [Indexed: 10/18/2022]
Abstract
Many studies have identified changes in gene expression in brains of schizophrenia patients and their altered molecular processes, but the findings in different datasets were inconsistent and diverse. Here we performed the most comprehensive analysis of gene expression patterns to explore the underlying mechanisms and the potential biomarkers for early diagnosis in schizophrenia. We focused on 10 gene expression datasets in post-mortem human brain samples of schizophrenia downloaded from gene expression omnibus (GEO) database using the integrated bioinformatics analyses including robust rank aggregation (RRA) algorithm, Weighted gene co-expression network analysis (WGCNA) and CIBERSORT. Machine learning algorithm was used to construct the risk prediction model for early diagnosis of schizophrenia. We identified 15 key genes (SLC1A3, AQP4, GJA1, ALDH1L1, SOX9, SLC4A4, EGR1, NOTCH2, PVALB, ID4, ABCG2, METTL7A, ARC, F3 and EMX2) in schizophrenia by performing multiple bioinformatics analysis algorithms. Moreover, the interesting part of the study is that there is a correlation between the expression of hub genes and the immune infiltrating cells estimated by CIBERSORT. Besides, the risk prediction model was constructed by using both these genes and the immune cells with a high accuracy of 0.83 in the training set, and achieved a high AUC of 0.77 for the test set. Our study identified several potential biomarkers for diagnosis of SCZ based on multiple bioinformatics algorithms, and the constructed risk prediction model using these biomarkers achieved high accuracy. The results provide evidence for an improved understanding of the molecular mechanism of schizophrenia.
Collapse
Affiliation(s)
- Zhijun Li
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Xinwei Li
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Mengdi Jin
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Yang Liu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Yang He
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Ningning Jia
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Xingyao Cui
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Yane Liu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Guoyan Hu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Qiong Yu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China.
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Chang CY, Luo DZ, Pei JC, Kuo MC, Hsieh YC, Lai WS. Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia. Int J Mol Sci 2021; 22:ijms22105343. [PMID: 34069523 PMCID: PMC8160762 DOI: 10.3390/ijms22105343] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/14/2021] [Accepted: 05/14/2021] [Indexed: 12/16/2022] Open
Abstract
Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood–brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.
Collapse
Affiliation(s)
- Chia-Yuan Chang
- Department of Psychology, National Taiwan University, Taipei 10617, Taiwan; (C.-Y.C.); (D.-Z.L.); (J.-C.P.); (Y.-C.H.)
- Neurobiology and Cognitive Science Center, National Taiwan University, Taipei 10617, Taiwan;
| | - Da-Zhong Luo
- Department of Psychology, National Taiwan University, Taipei 10617, Taiwan; (C.-Y.C.); (D.-Z.L.); (J.-C.P.); (Y.-C.H.)
| | - Ju-Chun Pei
- Department of Psychology, National Taiwan University, Taipei 10617, Taiwan; (C.-Y.C.); (D.-Z.L.); (J.-C.P.); (Y.-C.H.)
| | - Ming-Che Kuo
- Neurobiology and Cognitive Science Center, National Taiwan University, Taipei 10617, Taiwan;
- Department of Neurology, National Taiwan University Hospital, Taipei 100225, Taiwan
| | - Yi-Chen Hsieh
- Department of Psychology, National Taiwan University, Taipei 10617, Taiwan; (C.-Y.C.); (D.-Z.L.); (J.-C.P.); (Y.-C.H.)
| | - Wen-Sung Lai
- Department of Psychology, National Taiwan University, Taipei 10617, Taiwan; (C.-Y.C.); (D.-Z.L.); (J.-C.P.); (Y.-C.H.)
- Neurobiology and Cognitive Science Center, National Taiwan University, Taipei 10617, Taiwan;
- Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei 10617, Taiwan
- Correspondence: ; Tel.: +886-2-3366-3112; Fax: +886-2-3362-9909
| |
Collapse
|
|
6
|
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.
Collapse
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.
| |
Collapse
|
|
7
|
Grimaldi M, Marino C, Buonocore M, Santoro A, Sommella E, Merciai F, Salviati E, De Rosa A, Nuzzo T, Errico F, Campiglia P, Usiello A, D'Ursi AM. Prenatal and Early Postnatal Cerebral d-Aspartate Depletion Influences l-Amino Acid Pathways, Bioenergetic processes, and Developmental Brain Metabolism. J Proteome Res 2020; 20:727-739. [PMID: 33274941 DOI: 10.1021/acs.jproteome.0c00622] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
d-Amino acids were believed to occur only in bacteria and invertebrates. Today, it is well known that d-amino acids are also present in mammalian tissues in a considerable amount. In particular, high levels of free d-serine (d-Ser) and d-aspartate (d-Asp) are found in the brain. While the functions of d-Ser are well known, many questions remain unanswered regarding the role of d-Asp in the central nervous system. d-Asp is very abundant at the embryonic stage, while it strongly decreases after birth because of the expression of d-aspartate oxidase (Ddo) enzyme, which catalyzes the oxidation of this d-amino acid into oxaloacetate, ammonium, and hydrogen peroxide. Pharmacologically, d-Asp acts as an endogenous agonist of N-methyl d-aspartate and mGlu5 receptors, which are known to control fundamental brain processes, including brain development, synaptic plasticity, and cognition. In this work, we studied a recently generated knockin mouse model (R26ddo/ddo), which was designed to express DDO beginning at the zygotic stage. This strategy enables d-Asp to be almost eliminated in both prenatal and postnatal lives. To understand which biochemical pathways are affected by depletion of d-Asp, in this study, we carried out a metabolomic and lipidomic study of ddo knockin brains at different stages of embryonic and postnatal development, combining nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) techniques. Our study shows that d-Asp deficiency in the brain influences amino acid pathways such as threonine, glycine, alanine, valine, and glutamate. Interestingly, d-Asp is also correlated with metabolites involved in brain development and functions such as choline, creatine, phosphocholine (PCho), glycerophosphocholine (GPCho), sphingolipids, and glycerophospholipids, as well as metabolites involved in brain energy metabolism, such as GPCho, glucose, and lactate.
Collapse
Affiliation(s)
| | - Carmen Marino
- PhD Program in Drug Discovery and Development, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Michela Buonocore
- PhD Program in Drug Discovery and Development, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Angelo Santoro
- PhD Program in Drug Discovery and Development, University of Salerno, 84084 Fisciano, Salerno, Italy
| | | | - Fabrizio Merciai
- PhD Program in Drug Discovery and Development, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Emanuela Salviati
- PhD Program in Drug Discovery and Development, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Arianna De Rosa
- Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy.,Department of Environmental, Biological and Pharmaceutical Science and Technologies (DISTABIF), University of Campania, L. Vanvitelli, 81100 Caserta, Italy
| | - Tommaso Nuzzo
- Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy.,Department of Environmental, Biological and Pharmaceutical Science and Technologies (DISTABIF), University of Campania, L. Vanvitelli, 81100 Caserta, Italy
| | - Francesco Errico
- Department of Agricultural Sciences, University of Naples "Federico II", Via Università, 100-80055 Portici, Italy
| | - Pietro Campiglia
- European Biomedical Research Institute of Salerno, Via De Renzi 50, 84125 Salerno, Italy
| | - Alessandro Usiello
- Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy.,Department of Environmental, Biological and Pharmaceutical Science and Technologies (DISTABIF), University of Campania, L. Vanvitelli, 81100 Caserta, Italy
| | | |
Collapse
|
|
8
|
Sun T, Huang GY, Wang ZH, Teng SH, Cao YH, Sun JL, Hanif Q, Chen NB, Lei CZ, Liao YY. Selection signatures of Fuzhong Buffalo based on whole-genome sequences. BMC Genomics 2020; 21:674. [PMID: 32993537 PMCID: PMC7526191 DOI: 10.1186/s12864-020-07095-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Fuzhong buffalo, a native breed of Guangxi Zhuang Autonomous Region, is traditionally used as a draft animal to provide farm power in the rice cultivation. In addition, the Fuzhong buffalo also prepared for the bullfighting festival organized by the locals. The detection of the selective signatures in its genome can help in elucidating the selection mechanisms in its stamina and muscle development of a draft animal. RESULTS In this study, we analyzed 27 whole genomes of buffalo (including 15 Fuzhong buffalo genomes and 12 published buffalo genomes from Upper Yangtze region). The ZHp, ZFst, π-Ratio, and XP-EHH statistics were used to identify the candidate signatures of positive selection in Fuzhong buffalo. Our results detected a set of candidate genes involving in the pathways and GO terms associated with the response to exercise (e.g., ALDOA, STAT3, AKT2, EIF4E2, CACNA2D2, TCF4, CDH2), immunity (e.g., PTPN22, NKX2-3, PIK3R1, ITK, TMEM173), nervous system (e.g., PTPN21, ROBO1, HOMER1, MAGI2, SLC1A3, NRG3, SNAP47, CTNNA2, ADGRL3). In addition, we also identified several genes related to production and growth traits (e.g., PHLPP1, PRKN, MACF1, UCN3, RALGAPA1, PHKB, PKD1L). Our results depicted several pathways, GO terms, and candidate genes to be associated with response to exercise, immunity, nervous system, and growth traits. CONCLUSIONS The selective sweep analysis of the Fuzhong buffalo demonstrated positive selection pressure on potential target genes involved in behavior, immunity, and growth traits, etc. Our findings provided a valuable resource for future research on buffalo breeding and an insight into the mechanisms of artificial selection.
Collapse
Affiliation(s)
- Ting Sun
- Animal Husbandry Institute of Guangxi Zhuang Autonomous Region, Guangxi Key Laboratory of Livestock Genetic Improvement, Nanning, 530001, China.,College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Guang-Yun Huang
- Animal Husbandry Institute of Guangxi Zhuang Autonomous Region, Guangxi Key Laboratory of Livestock Genetic Improvement, Nanning, 530001, China
| | - Zi-Hao Wang
- Animal Husbandry Institute of Guangxi Zhuang Autonomous Region, Guangxi Key Laboratory of Livestock Genetic Improvement, Nanning, 530001, China
| | - Shao-Hua Teng
- Animal Husbandry Institute of Guangxi Zhuang Autonomous Region, Guangxi Key Laboratory of Livestock Genetic Improvement, Nanning, 530001, China
| | - Yan-Hong Cao
- Animal Husbandry Institute of Guangxi Zhuang Autonomous Region, Guangxi Key Laboratory of Livestock Genetic Improvement, Nanning, 530001, China
| | - Jun-Li Sun
- Animal Husbandry Institute of Guangxi Zhuang Autonomous Region, Guangxi Key Laboratory of Livestock Genetic Improvement, Nanning, 530001, China
| | - Quratulain Hanif
- Computational Biology Laboratory, Agricultural Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan.,Department of Biotechnology, Pakistan Institute of Engineering and Applied Sciences, Nilore, Islamabad, Pakistan
| | - Ning-Bo Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Chu-Zhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Yu-Ying Liao
- Animal Husbandry Institute of Guangxi Zhuang Autonomous Region, Guangxi Key Laboratory of Livestock Genetic Improvement, Nanning, 530001, China.
| |
Collapse
|
|
9
|
Li W, Su X, Chen T, Li Z, Yang Y, Zhang L, Liu Q, Shao M, Zhang Y, Ding M, Lu Y, Yu H, Fan X, Song M, Lv L. Solute Carrier Family 1 ( SLC1A1) Contributes to Susceptibility and Psychopathology Symptoms of Schizophrenia in the Han Chinese Population. Front Psychiatry 2020; 11:559210. [PMID: 33173509 PMCID: PMC7538510 DOI: 10.3389/fpsyt.2020.559210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/31/2020] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamate hypothesis describes one possible pathogenesis of SZ. The solute carrier family 1 gene (SLC1A1) is one of several genes thought to play a critical role in regulating the glutamatergic system and is strongly implicated in the pathophysiology of SZ. In this study, we identify polymorphisms of the SLC1A1 gene that may confer susceptibility to SZ in the Han Chinese population. METHODS We genotyped 36 single-nucleotide polymorphisms (SNPs) using Illumina GoldenGate assays on a BeadStation 500G Genotyping System in 528 paranoid SZ patients and 528 healthy controls. Psychopathology was rated by the Positive and Negative Symptom Scale. RESULTS Significant associations were found in genotype and allele frequencies for SNPs rs10815017 (p = 0.002, 0.030, respectively) and rs2026828 (p = 0.020, 0.005, respectively) between SZ and healthy controls. There were significant associations in genotype frequency at rs6476875 (p = 0.020) and rs7024664 (p = 0.021) and allele frequency at rs3780412 (p = 0.026) and rs10974573 (p = 0.047) between SZ and healthy controls. Meanwhile, significant differences were found in genotype frequency at rs10815017 (p = 0.015), rs2026828 (p = 0.011), and rs3780411 (p = 0.040) in males, and rs7021569 in females (p = 0.020) between cases and controls when subdivided by gender. Also, significant differences were found in allele frequency at rs2026828 (p = 0.003), and rs7021569 (p = 0.045) in males, and rs10974619 in females (p = 0.044). However, those associations disappeared after Bonferroni's correction (p's > 0.05). Significant associations were found in the frequencies of four haplotypes (AA, CA, AGA, and GG) between SZ and healthy controls (χ 2 = 3.974, 7.433, 4.699, 4.526, p = 0.046, 0.006, 0.030, 0.033, respectively). There were significant associations between rs7032326 genotypes and PANSS total, positive symptoms, negative symptoms, and general psychopathology in SZ (p = 0.002, 0.011, 0.028, 0.008, respectively). CONCLUSION The present study provides further evidence that SLC1A1 may be not a susceptibility gene for SZ. However, the genetic variations of SLC1A1 may affect psychopathology symptoms.
Collapse
Affiliation(s)
- Wenqiang Li
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Xi Su
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Tengfei Chen
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Zhen Li
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Yongfeng Yang
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Luwen Zhang
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Qing Liu
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Minglong Shao
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Yan Zhang
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Minli Ding
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China
| | - Yanli Lu
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China
| | - Hongyan Yu
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China
| | - Xiaoduo Fan
- Department of Psychiatry, University of Massachusetts Medical School/UMass Memorial Medical Center, Worcester, MA, United States
| | - Meng Song
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Luxian Lv
- Department of Mental Health, The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| |
Collapse
|
|
10
|
Tsuang DW, Greenwood TA, Jayadev S, Davis M, Shutes-David A, Bird TD. A Genetic Study of Psychosis in Huntington's Disease: Evidence for the Involvement of Glutamate Signaling Pathways. J Huntingtons Dis 2019; 7:51-59. [PMID: 29480208 DOI: 10.3233/jhd-170277] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. OBJECTIVE To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. METHODS DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. RESULTS Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. CONCLUSIONS This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.
Collapse
Affiliation(s)
- Debby W Tsuang
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.,Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.,Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA
| | - Tiffany A Greenwood
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Suman Jayadev
- Department of Neurology, University of Washington, Seattle, WA, USA
| | - Marie Davis
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.,Department of Neurology, University of Washington, Seattle, WA, USA
| | - Andrew Shutes-David
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.,Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Thomas D Bird
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.,Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.,Department of Neurology, University of Washington, Seattle, WA, USA
| |
Collapse
|
|
11
|
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: 90] [Impact Index Per Article: 12.9] [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.
Collapse
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
| |
Collapse
|
|
12
|
Abstract
The presence of obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorders (OCD) in schizophrenia is frequent, and a new clinical entity has been proposed for those who show the dual diagnosis: the schizo-obsessive disorder. This review scrutinizes the literature across the main academic databases, and provides an update on different aspects of schizo-obsessive spectrum disorders, which include schizophrenia, schizotypal personality disorder (SPD) with OCD, OCD with poor insight, schizophrenia with OCS, and schizophrenia with OCD (schizo-obsessive disorder). An epidemiological discussion on the discrepancies observed in the prevalence of OCS and OCD in schizophrenia across time is provided, followed by an overview of the main clinical and phenomenological features of the disorder in comparison to the primary conditions under a spectral perspective. An updated and comparative analysis of the main genetic, neurobiological, neurocognitive, and pharmacological treatment aspects for the schizo-obsessive spectrum is provided, and a discussion on endophenotypic markers is introduced in order to better understand its substrate. There is sufficient evidence in the literature to demonstrate the clinical relevance of the schizo-obsessive spectrum, although little is known about the neurobiology, genetics, and neurocognitive aspects of these groups. The pharmacological treatment of these patients is still challenging, and efforts to search for possible specific endophenotypic markers would open new avenues in the knowledge of schizo-obsessive spectrum.
Collapse
|
|
13
|
Abousaab A, Warsi J, Elvira B, Lang F. Caveolin-1 Sensitivity of Excitatory Amino Acid Transporters EAAT1, EAAT2, EAAT3, and EAAT4. J Membr Biol 2015; 249:239-49. [PMID: 26690923 DOI: 10.1007/s00232-015-9863-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/07/2015] [Indexed: 10/22/2022]
Abstract
Excitatory amino acid transporters EAAT1 (SLC1A3), EAAT2 (SLC1A2), EAAT3 (SLC1A1), and EAAT4 (SLC1A6) serve to clear L-glutamate from the synaptic cleft and are thus important for the limitation of neuronal excitation. EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. To this end cRNA encoding EAAT1, EAAT2, EAAT3, or EAAT4 was injected into Xenopus oocytes without or with additional injection of cRNA encoding caveolin-1. The L-glutamate (2 mM)-induced inward current (I Glu) was taken as a measure of glutamate transport. As a result, I Glu was observed in EAAT1-, EAAT2-, EAAT3-, or EAAT4-expressing oocytes but not in water-injected oocytes, and was significantly decreased by coexpression of caveolin-1. Caveolin-1 decreased significantly the maximal transport rate. Treatment of EAATs-expressing oocytes with brefeldin A (5 µM) was followed by a decrease in conductance, which was similar in oocytes expressing EAAT together with caveolin-1 as in oocytes expressing EAAT1-4 alone. Thus, caveolin-1 apparently does not accelerate transporter protein retrieval from the cell membrane. In conclusion, caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4.
Collapse
Affiliation(s)
- Abeer Abousaab
- Department of Physiology I, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany
| | - Jamshed Warsi
- Department of Physiology I, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany
| | - Bernat Elvira
- Department of Physiology I, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany
| | - Florian Lang
- Department of Physiology I, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
| |
Collapse
|
|
14
|
Wang C, Aleksic B, Ozaki N. Glia-related genes and their contribution to schizophrenia. Psychiatry Clin Neurosci 2015; 69:448-61. [PMID: 25759284 DOI: 10.1111/pcn.12290] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/08/2015] [Indexed: 12/24/2022]
Abstract
Schizophrenia, a debilitating disease with 1% prevalence in the general population, is characterized by major neuropsychiatric symptoms, including delusions, hallucinations, and deficits in emotional and social behavior. Previous studies have directed their investigations on the mechanism of schizophrenia towards neuronal dysfunction and have defined schizophrenia as a 'neuron-centric' disorder. However, along with the development of genetics and systematic biology approaches in recent years, the crucial role of glial cells in the brain has also been shown to contribute to the etiopathology of schizophrenia. Here, we summarize comprehensive data that support the involvement of glial cells (including oligodendrocytes, astrocytes, and microglial cells) in schizophrenia and list several acknowledged glia-related genes or molecules associated with schizophrenia. Instead of purely an abnormality of neurons in schizophrenia, an additional 'glial perspective' provides us a novel and promising insight into the causal mechanisms and treatment for this disease.
Collapse
Affiliation(s)
- Chenyao Wang
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Branko Aleksic
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
15
|
Borrás J, Salker MS, Elvira B, Warsi J, Fezai M, Hoseinzadeh Z, Lang F. SPAK and OSR1 Sensitivity of Excitatory Amino Acid Transporter EAAT3. Nephron Clin Pract 2015; 130:221-8. [PMID: 26112741 DOI: 10.1159/000433567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 05/20/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Kinases involved in the regulation of epithelial transport include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1). SPAK and OSR1 are both regulated by WNK (with-no-K(Lys)) kinases. The present study explored whether SPAK and/or OSR1 influence the excitatory amino acid transporter EAAT3, which accomplishes glutamate and aspartate transport in kidney, intestine and brain. METHODS cRNA encoding EAAT3 was injected into Xenopus laevis oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active (T233E)SPAK, WNK insensitive (T233A)SPAK, catalytically inactive (D212A)SPAK, wild-type OSR1, constitutively active (T185E)OSR1, WNK insensitive (T185A)OSR1 and catalytically inactive (D164A)OSR1. Glutamate-induced current was taken as measure of electrogenic glutamate transport and was quantified utilizing dual electrode voltage clamp. Furthermore, Ussing chamber was employed to determine glutamate transport in the intestine from gene-targeted mice carrying WNK insensitive SPAK (spak(tg/tg)) and from corresponding wild-type mice (spak(+/+)). RESULTS EAAT3 activity was significantly decreased by wild-type SPAK and (T233E)SPAK, but not by (T233A)SPAK and (D212A)SPAK. SPAK decreased maximal transport rate without affecting significantly affinity of the carrier. Similarly, EAAT3 activity was significantly downregulated by wild-type OSR1 and (T185E)OSR1, but not by (T185A)OSR1 and (D164A)OSR1. Again OSR1 decreased maximal transport rate without affecting significantly affinity of the carrier. Intestinal electrogenic glutamate transport was significantly lower in spak(+/+) than in spak(tg/tg) mice. CONCLUSION Both, SPAK and OSR1 are negative regulators of EAAT3 activity.
Collapse
Affiliation(s)
- José Borrás
- Department of Physiology I, University of Tübingen, Tubingen, Germany
| | | | | | | | | | | | | |
Collapse
|
|
16
|
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.
Collapse
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.
| |
Collapse
|
|
17
|
Kaur H, Jajodia A, Grover S, Baghel R, Jain S, Kukreti R. Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness. Am J Med Genet B Neuropsychiatr Genet 2014; 165B:635-46. [PMID: 25209194 DOI: 10.1002/ajmg.b.32268] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 08/07/2014] [Indexed: 12/11/2022]
Abstract
Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69-41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30-38.12 and OR = 13.5; 95%CI = 3.03-121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions.
Collapse
Affiliation(s)
- Harpreet Kaur
- Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India
| | | | | | | | | | | |
Collapse
|
|
18
|
Antipsychotic treatment modulates glutamate transport and NMDA receptor expression. Eur Arch Psychiatry Clin Neurosci 2014; 264 Suppl 1:S67-82. [PMID: 25214389 DOI: 10.1007/s00406-014-0534-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 09/02/2014] [Indexed: 12/21/2022]
Abstract
Schizophrenia patients often suffer from treatment-resistant cognitive and negative symptoms, both of which are influenced by glutamate neurotransmission. Innovative therapeutic strategies such as agonists at metabotropic glutamate receptors or glycin reuptake inhibitors try to modulate the brain's glutamate network. Interactions of amino acids with monoamines have been described on several levels, and first- and second-generation antipsychotic agents (FGAs, SGAs) are known to exert modulatory effects on the glutamatergic system. This review summarizes the current knowledge on effects of FGAs and SGAs on glutamate transport and receptor expression derived from pharmacological studies. Such studies serve as a control for molecular findings in schizophrenia brain tissue and are clinically relevant. Moreover, they may validate animal models for psychosis, foster basic research on antipsychotic substances and finally lead to a better understanding of how monoaminergic and amino acid neurotransmissions are intertwined. In the light of these results, important differences dependent on antipsychotic substances, dosage and duration of treatment became obvious. While some post-mortem findings might be confounded with multifold drug effects, others are unlikely to be influenced by antipsychotic treatment and could represent important markers of schizophrenia pathophysiology. In similarity to the convergence of toxic and psychotomimetic effects of dopaminergic, serotonergic and anti-glutamatergic substances, the therapeutic mechanisms of SGAs might merge on a yet to be defined molecular level. In particular, serotonergic effects of SGAs, such as an agonism at 5HT1A receptors, represent important targets for further clinical research.
Collapse
|
|
19
|
Lu W, Wu H, Cai J, Wang Z, Yi Z, Yu S, Fang Y, Zhang C. Lack of association of SLC1A1 variants with schizophrenia in Chinese Han population. Psychiatry Res 2013; 210:669-71. [PMID: 23931931 DOI: 10.1016/j.psychres.2013.07.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Revised: 07/04/2013] [Accepted: 07/08/2013] [Indexed: 12/27/2022]
Abstract
In this study, we analyzed four single nucleotide polymorphisms (SNPs) (rs10491734, rs2228622, rs301430 and rs301443) of the solute carrier family 1 gene (SLC1A1) in a set of 616 schizophrenia patients and 638 matched healthy controls of Han Chinese descent. No significant differences of genotype or allele distribution were identified between the patients and controls. Our data suggest that SLC1A1 is unlikely to be a major susceptibility gene for schizophrenia in Han Chinese.
Collapse
Affiliation(s)
- Weihong Lu
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Schirmbeck F, Zink M. Comorbid obsessive-compulsive symptoms in schizophrenia: contributions of pharmacological and genetic factors. Front Pharmacol 2013; 4:99. [PMID: 23950745 PMCID: PMC3738863 DOI: 10.3389/fphar.2013.00099] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 07/22/2013] [Indexed: 12/17/2022] Open
Abstract
A large subgroup of around 25% of schizophrenia patients suffers from obsessive-compulsive symptoms (OCS) and about 12% fulfill the diagnostic criteria of an obsessive-compulsive disorder (OCD). The additional occurrence of OCS is associated with high subjective burden of disease, additional neurocognitive impairment, poorer social and vocational functioning, greater service utilization and high levels of anxiety and depression. Comorbid patients can be assigned to heterogeneous subgroups. One hypothesis assumes that second generation antipsychotics (SGAs), most importantly clozapine, might aggravate or even induce second-onset OCS. Several arguments support this assumption, most importantly the observed chronological order of first psychotic manifestation, start of treatment with clozapine and onset of OCS. In addition, correlations between OCS-severity and dose and serum levels and duration of clozapine treatment hint toward a dose-dependent side effect. It has been hypothesized that genetic risk-factors dispose patients with schizophrenia to develop OCS. One study in a South Korean sample reported associations with polymorphisms in the gene SLC1A1 (solute carrier family 1A1) and SGA-induced OCS. However, this finding could not be replicated in European patients. Preliminary results also suggest an involvement of polymorphisms in the BDNF gene (brain-derived neurotrophic factor) and an interaction between markers of SLC1A1 and the gene DLGAP3 (disc large associated protein 3) as well as GRIN2B (N-methyl-D-aspartate receptor subunit 2B). Further research of well-defined samples, in particular studies investigating possible interactions of genetic risk-constellations and pharmacodynamic properties, are needed to clarify the assumed development of SGA-induced OCS. Results might improve pathogenic concepts and facilitate the definition of at risk populations, early detection and monitoring of OCS as well as multimodal therapeutic interventions.
Collapse
Affiliation(s)
- Frederike Schirmbeck
- Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Faculty Medicine Mannheim, Heidelberg University Mannheim, Germany
| | | |
Collapse
|
|
21
|
Almilaji A, Munoz C, Pakladok T, Alesutan I, Feger M, Föller M, Lang UE, Shumilina E, Lang F. Klotho sensitivity of the neuronal excitatory amino acid transporters EAAT3 and EAAT4. PLoS One 2013; 8:e70988. [PMID: 23923038 PMCID: PMC3726597 DOI: 10.1371/journal.pone.0070988] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 07/01/2013] [Indexed: 01/02/2023] Open
Abstract
Klotho, a transmembrane protein, which can be cleaved off as β-glucuronidase and hormone, is released in both, kidney and choroid plexus and encountered in blood and cerebrospinal fluid. Klotho deficiency leads to early appearance of age-related disorders and premature death. Klotho may modify transport by inhibiting 1,25(OH)2D3 formation or by directly affecting channel and carrier proteins. The present study explored whether Klotho influences the activity of the Na+-coupled excitatory amino acid transporters EAAT3 and EAAT4, which are expressed in kidney (EAAT3), intestine (EAAT3) and brain (EAAT3 and EAAT4). To this end, cRNA encoding EAAT3 or EAAT4 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho. EAAT expressing Xenopus oocytes were further treated with recombinant human β-Klotho protein with or without β-glucuronidase inhibitor D-saccharic acid 1,4-lactone monohydrate (DSAL). Electrogenic excitatory amino acid transport was determined as L-glutamate-induced current (Iglu) in two electrode voltage clamp experiments. EAAT3 and EAAT4 protein abundance in the Xenopus oocyte cell membrane was visualized by confocal microscopy and quantified utilizing chemiluminescence. As a result, coexpression of Klotho cRNA significantly increased Iglu in both, EAAT3 or EAAT4-expressing Xenopus oocytes. Klotho cRNA coexpression significantly increased the maximal current and cell membrane protein abundance of both EAAT3 and EAAT4. The effect of Klotho coexpression on EAAT3 and EAAT4 activity was mimicked by treating EAAT3 or EAAT4-expressing Xenopus oocytes with recombinant human β-Klotho protein. The effects of Klotho coexpression and of treatment with recombinant human β-Klotho protein were both abrogated in the presence of DSAL (10 µM). In conclusion, Klotho is a novel, powerful regulator of the excitatory amino acid transporters EAAT3 and EAAT4.
Collapse
Affiliation(s)
- Ahmad Almilaji
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Carlos Munoz
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | | | - Ioana Alesutan
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Martina Feger
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Michael Föller
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Undine E. Lang
- Department of Psychiatry and Psychotherapy, University Psychiatric Clinics (UPK) Basel, Basel, Switzerland
| | | | - Florian Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany
- * E-mail:
| |
Collapse
|
|
22
|
Isoforms of the neuronal glutamate transporter gene, SLC1A1/EAAC1, negatively modulate glutamate uptake: relevance to obsessive-compulsive disorder. Transl Psychiatry 2013; 3:e259. [PMID: 23695234 PMCID: PMC3669922 DOI: 10.1038/tp.2013.35] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The SLC1A1 gene, which encodes the neuronal glutamate transporter, EAAC1, has consistently been implicated in obsessive-compulsive disorder (OCD) in genetic studies. Moreover, neuroimaging, biochemical and clinical studies support a role for glutamatergic dysfunction in OCD. Although SLC1A1 is an excellent candidate gene for OCD, little is known about its regulation at the genomic level. Here, we report the identification and characterization of three alternative SLC1A1/EAAC1 mRNAs: a transcript derived from an internal promoter, termed P2 to distinguish it from the transcript generated by the primary promoter (P1), and two alternatively spliced mRNAs: ex2skip, which is missing exon 2, and ex11skip, which is missing exon 11. All isoforms inhibit glutamate uptake from the full-length EAAC1 transporter. Ex2skip and ex11skip also display partial colocalization and interact with the full-length EAAC1 protein. The three isoforms are evolutionarily conserved between human and mouse, and are expressed in brain, kidney and lymphocytes under nonpathological conditions, suggesting that the isoforms are physiological regulators of EAAC1. Moreover, under specific conditions, all SLC1A1 transcripts were differentially expressed in lymphocytes derived from subjects with OCD compared with controls. These initial results reveal the complexity of SLC1A1 regulation and the potential clinical utility of profiling glutamatergic gene expression in OCD and other psychiatric disorders.
Collapse
|
|
23
|
Polymorphisms in the glutamate transporter gene SLC1A1 and obsessive-compulsive symptoms induced by second-generation antipsychotic agents. Psychiatr Genet 2013; 22:245-52. [PMID: 22531293 DOI: 10.1097/ypg.0b013e328353fbee] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND A large subgroup of schizophrenic patients develops obsessive-compulsive symptoms (OCS) during treatment with second-generation antipsychotics (SGA). A genetic risk factor for these secondary OCS was recently described in the gene SLC1A1 encoding the neuronal glutamate transporter excitatory amino acid carrier 1. The aim of this study was to replicate these findings in a European sample. METHODS A total of 103 schizophrenic patients treated with SGAs were included. Three single nucleotide polymorphisms in SLC1A1 (rs2228622, rs3780412 and rs3780413), which had been associated with SGA-induced OCS, were investigated. Single marker and haplotype analyses were tested with logistic regressions using age, sex and medication type as covariates. RESULTS Treatment with markedly antiserotonergic SGAs such as clozapine was more prevalent in the subgroup of patients with comorbid OCS (P<0.001). The dosage and duration of clozapine treatment correlated significantly with the severity of OCS. In contrast to the Asian sample, no genetic associations were found with OCS. CONCLUSION Larger samples are necessary to unravel the interplay of pharmacological and genetic risk factors for OCS in schizophrenia.
Collapse
|
|
24
|
Regulation of the glutamate transporter EAAT3 by mammalian target of rapamycin mTOR. Biochem Biophys Res Commun 2012; 421:159-63. [PMID: 22483750 DOI: 10.1016/j.bbrc.2012.03.109] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 03/21/2012] [Indexed: 01/11/2023]
Abstract
The serine/threonine kinase mammalian target of rapamycin (mTOR) is stimulated by insulin, growth factors and nutrients and confers survival of several cell types. The kinase has previously been shown to stimulate amino acid uptake. In neurons, the cellular uptake of glutamate by the excitatory amino-acid transporters (EAATs) decreases excitation and thus confers protection against excitotoxicity. In epithelia, EAAT3 accomplishes transepithelial glutamate and aspartate transport. The present study explored, whether mTOR regulates EAAT3 (SLC1A1). To this end, cRNA encoding EAAT3 was injected into Xenopus oocytes with or without cRNA encoding mTOR and the glutamate induced current (I(glu)), a measure of glutamate transport, determined by dual electrode voltage clamp. Moreover, EAAT3 protein abundance was determined utilizing chemiluminescence. As a result, I(glu) was observed in Xenopus oocytes expressing EAAT3 but not in water injected oocytes. Coexpression of mTOR significantly increased I(glu), an effect reversed by rapamycin (100 nM). mTOR coexpression increased EAAT3 protein abundance in the cell membrane. The decay of I(glu) following inhibition of carrier insertion with brefeldin A in oocytes coexpressing EAAT3 with mTOR was similar in the presence and absence of rapamycin (100 nM). In conclusion, mTOR is a novel powerful regulator of EAAT3 and may thus contribute to protection against neuroexcitotoxicity.
Collapse
|
|
25
|
Horiuchi Y, Iida S, Koga M, Ishiguro H, Iijima Y, Inada T, Watanabe Y, Someya T, Ujike H, Iwata N, Ozaki N, Kunugi H, Tochigi M, Itokawa M, Arai M, Niizato K, Iritani S, Kakita A, Takahashi H, Nawa H, Arinami T. Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2012; 159B:30-7. [PMID: 22095641 DOI: 10.1002/ajmg.b.31249] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2011] [Accepted: 10/18/2011] [Indexed: 11/10/2022]
Abstract
Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P = 5 × 10(-5) , allelic corrected P = 2.5 × 10(-4) , allelic odds ratio, 1.30; 95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P = 0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia.
Collapse
Affiliation(s)
- Yasue Horiuchi
- Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Hosseinzadeh Z, Bhavsar SK, Sopjani M, Alesutan I, Saxena A, Dërmaku-Sopjani M, Lang F. Regulation of the glutamate transporters by JAK2. Cell Physiol Biochem 2011; 28:693-702. [PMID: 22178881 DOI: 10.1159/000335763] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2011] [Indexed: 01/13/2023] Open
Abstract
The Janus-activated kinase-2 JAK2 is involved in the signaling of leptin and erythropoietin receptors and mediates neuroprotective effects of the hormones. In theory, JAK2 could be effective through modulation of the glutamate transporters, carriers accounting for the clearance of glutamate released during neurotransmission. The present study thus elucidated the effect of JAK2 on the glutamate transporters EAAT1, EAAT2, EAAT3 and EAAT4. To this end, cRNA encoding the carriers was injected into Xenopus oocytes with or without cRNA encoding JAK2 and glutamate transport was estimated from glutamate induced current (I(glu)). I(glu) was observed in Xenopus oocytes expressing EAAT1 or EAAT2 or EAAT3 or EAAT4, but not in water injected oocytes. Coexpression of JAK2 resulted in an increase of I(glu) by 83% (EAAT1), 67% (EAAT2), 42% (EAAT3) and 126% (EAAT4). As shown for EAAT4 expressing Xenopus oocytes, the effect of JAK2 was mimicked by gain of function mutation (V617F)JAK2 but not by the inactive mutant (K882E)JAK2. Incubation with JAK2 inhibitor AG490 (40 μM) resulted in a gradual decrease of I(glu) by 53%, 79% and 92% within 3, 6 and 24 hours. Confocal microscopy and chemiluminescence analysis revealed that JAK2 coexpression increased EAAT4 protein abundance in the cell membrane. Disruption of transcription did not appreciably modify the up-regulation of I(glu) in EAAT4 expressing oocytes. The decay of I(glu) following inhibition of carrier insertion with brefeldin A was similar in oocytes expressing EAAT4 + JAK2 and oocytes expressing EAAT4 alone, indicating that JAK2 did not appreciably affect carrier retrieval from the membrane. In conclusion, JAK2 is a novel powerful regulator of glutamate transporters and thus participates in the protection against excitotoxicity.
Collapse
Affiliation(s)
- Zohreh Hosseinzadeh
- Department of Physiology, University of Tübingen, Gmelinstrasse 5, Tübingen, Germany
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Takebayashi Y, Ohnuma T, Hanzawa R, Shibata N, Maeshima H, Baba H, Hatano T, Hotta Y, Kitazawa M, Higa M, Arai H. No genetic association between SLC7A10 and Japanese patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:1965-8. [PMID: 21888942 DOI: 10.1016/j.pnpbp.2011.08.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2011] [Revised: 08/17/2011] [Accepted: 08/17/2011] [Indexed: 10/17/2022]
Abstract
Disrupted glutamatergic neurotransmission may be a pathophysiological feature in the brains from patients with schizophrenia, and glutamatergic amino acids including D-serine have been found to be involved in pathophysiology. Endogenous and exogenous D-serine have shown potential as biological markers for the pathophysiology of schizophrenia and especially as a therapeutic strategy in treatment-resistant schizophrenia (TRS). This is the first study investigating whether SLC7A10, a d-serine transporter gene, is associated with schizophrenia in Japanese patients. We investigated the association between schizophrenia in Japanese patients with SLC7A10 using six tag single nucleotide polymorphisms (SNPs). Results failed to show any association between Japanese schizophrenia and each individual SNP or with two-, three-, or four-window haplotype analyses. We also investigated whether SLC7A10 contributes to TRS in Japanese participants. Results showed no association. In conclusion, SLC7A10 had no apparent degree of association with schizophrenia as a candidate susceptibility gene in the disease per se.
Collapse
Affiliation(s)
- Yuto Takebayashi
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
López-Bayghen E, Ortega A. Glial glutamate transporters: New actors in brain signaling. IUBMB Life 2011; 63:816-23. [DOI: 10.1002/iub.536] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Accepted: 06/10/2011] [Indexed: 01/10/2023]
|
|
29
|
Segnitz N, Ferbert T, Schmitt A, Gass P, Gebicke-Haerter PJ, Zink M. Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain. Psychopharmacology (Berl) 2011; 217:127-42. [PMID: 21484241 DOI: 10.1007/s00213-011-2262-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2010] [Accepted: 03/13/2011] [Indexed: 12/25/2022]
Abstract
RATIONALE The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-methyl-D: -aspartate receptors (NMDA-R). Several therapeutic strategies address NMDA-R function and the effects of antipsychotic agents on NMDA-R expression have been described. Within the second-generation antipsychotics, the partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract the behavioral effects of NMDA-R antagonists. OBJECTIVES This study aims to investigate the effects of APZ on NMDA-R subunit expression and binding. METHODS We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kilogram of body weight. Gene expression of the NMDA-R subunits NR1, NR2A, NR2B, NR2C, and NR2D, respectively, was assessed by semiquantitative radioactive in situ hybridization and in parallel receptor binding using (3)H-MK-801 receptor autoradiography. RESULTS Increased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months), and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses of APZ, and the time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40-mg group and after 4 months in the 10-mg group. CONCLUSIONS The effects of APZ converge in enhanced NMDA receptor expression and a shift of subunit composition towards adult-type receptors. Our results confirm the regulatory connections between dopaminergic, serotonergic, and glutamatergic neurotransmissions with relevance for cognitive and negative symptoms of schizophrenia.
Collapse
Affiliation(s)
- Nina Segnitz
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, P.O. Box 122120, 68072 Mannheim, Germany
| | | | | | | | | | | |
Collapse
|
|
30
|
Genotype-phenotype relationship in three cases with overlapping 19p13.12 microdeletions. Eur J Hum Genet 2010; 18:1302-9. [PMID: 20648052 DOI: 10.1038/ejhg.2010.115] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We describe the detailed clinical and molecular characterization of three patients (aged 7, 8(4/12) and 31 years) with overlapping microdeletions in 19p13.12, extending to 19p13.13 in two cases. The patients share the following clinical features with a recently reported 10-year-old girl with a 19p13.12 microdeletion: mental retardation (MR), psychomotor and language delay, hearing impairment, brachycephaly, anteverted nares and ear malformations. All patients share a 359-kb deleted region in 19p13.12 harboring six genes (LPHN1, DDX39, CD97, PKN1, PTGER1 and GIPC1), several of which may be MR candidates because of their function and expression pattern. LPHN1 and PKN1 are the most appealing; LPHN1 for its interaction with Shank family proteins, and PKN1 because it is involved in a variety of functions in neurons, including cytoskeletal organization. Haploinsufficiency of GIPC1 may contribute to hearing impairment for its interaction with myosin VI. A behavioral phenotype was observed in all three patients; it was characterized by overactive disorder associated with MR and stereotyped movements (ICD10) in one patient and hyperactivity in the other two. As Ptger1-null mice show behavioral inhibition and impulsive aggression with defective social interaction, PTGER1 haploinsufficiency may be responsible for the behavioral traits observed in these patients.
Collapse
|
|
31
|
Sopjani M, Alesutan I, Dërmaku-Sopjani M, Fraser S, Kemp BE, Föller M, Lang F. Down-regulation of Na+-coupled glutamate transporter EAAT3 and EAAT4 by AMP-activated protein kinase. J Neurochem 2010; 113:1426-35. [PMID: 20218975 DOI: 10.1111/j.1471-4159.2010.06678.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The glutamate transporters EAAT3 and EAAT4 are expressed in neurons. They contribute to the cellular uptake of glutamate and aspartate and thus to the clearance of the excitatory transmitters from the extracellular space. During ischemia, extracellular accumulation of glutamate may trigger excitotoxicity. Energy depletion leads to activation of the AMP-activated protein kinase (AMPK), a kinase enhancing energy production and limiting energy expenditure. The present study thus explored the possibility that AMPK regulates EAAT3 and/or EAAT4. To this end, EAAT3 or EAAT4 were expressed in Xenopus oocytes with or without AMPK and electrogenic glutamate transport determined by dual electrode voltage clamp. In EAAT3- and in EAAT4-expressing oocytes glutamate generated a current (I(g)), which was half maximal (K(M)) at 74 microM (EAAT3) or at 4 microM (EAAT4) glutamate. Co-expression of constitutively active (gammaR70Q)AMPK or of wild type AMPK did not affect K(M) but significantly decreased the maximal I(g) in both EAAT3- (by 34%) and EAAT4- (by 49%) expressing oocytes. Co-expression of the inactive mutant (alphaK45R)AMPK [alpha1(K45R)beta1gamma1] did not appreciably affect I(g). According to confocal microscopy and chemiluminescence co-expression of (gammaR70Q)AMPK or of wild type AMPK reduced the membrane abundance of EAAT3 and EAAT4. The observations show that AMPK down-regulates Na(+)-coupled glutamate transport.
Collapse
Affiliation(s)
- Mentor Sopjani
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | | | | | | | | | | | | |
Collapse
|
|
32
|
Cherlyn SYT, Woon PS, Liu JJ, Ong WY, Tsai GC, Sim K. Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance. Neurosci Biobehav Rev 2010; 34:958-77. [PMID: 20060416 DOI: 10.1016/j.neubiorev.2010.01.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Revised: 01/01/2010] [Accepted: 01/04/2010] [Indexed: 12/31/2022]
Abstract
Schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time.
Collapse
Affiliation(s)
- Suat Ying Tan Cherlyn
- Institute of Mental Health/Woodbridge Hospital, 10 Buangkok View, Singapore 539747, Singapore
| | | | | | | | | | | |
Collapse
|
|
33
|
Segnitz N, Schmitt A, Gebicke-Härter PJ, Zink M. Differential expression of glutamate transporter genes after chronic oral treatment with aripiprazole in rats. Neurochem Int 2009; 55:619-28. [DOI: 10.1016/j.neuint.2009.06.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2009] [Revised: 06/03/2009] [Accepted: 06/04/2009] [Indexed: 01/20/2023]
|
|
34
|
Fedorenko O, Tang C, Sopjani M, Föller M, Gehring EM, Strutz-Seebohm N, Ureche ON, Ivanova S, Semke A, Lang F, Seebohm G, Lang UE. PIP5K2A-dependent regulation of excitatory amino acid transporter EAAT3. Psychopharmacology (Berl) 2009; 206:429-35. [PMID: 19644675 DOI: 10.1007/s00213-009-1621-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2009] [Accepted: 07/09/2009] [Indexed: 01/20/2023]
Abstract
INTRODUCTION According to previous observations, the gene encoding the phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) is associated with schizophrenia. Specifically, the mutation (N251S)PIP5K2A has been discovered in schizophrenic patients but not in healthy individuals. A defect of the excitatory amino acid transporter EAAT3 has similarly been implicated in the development of schizophrenia. The present study thus explored whether PIP5K2A is involved in the regulation of EAAT3 activity. MATERIALS AND METHODS EAAT3 was expressed in Xenopus oocytes either without or with PIP5K2A, and EAAT3 transporter activity was estimated from the glutamate (2-mM)-induced current (I(glu)) in dual electrode voltage clamp experiments. EAAT3 protein abundance in the cell membrane was estimated by Western blotting and confocal microscopy. RESULTS In EAAT3-expressing oocytes, I(glu) was enhanced by coexpression of wild type PIP5K2A. Coexpression of the schizophrenia-associated mutant (N251S)PIP5K2A significantly decreased I(glu) in oocytes expressing EAAT3 with or without additional expression of wild type PIP5K2A. Thus, (N251S)PIP5K2A exerts a dominant inhibitory effect. DISCUSSION Membrane abundance of EAAT3 was increased by wild type PIP5K2A and decreased by (N251S)PIP5K2A in both EAAT3-expressing oocytes and human embryonic kidney cells. The present observations disclose a novel mechanism of EAAT3 regulation, which may contribute to the deranged regulation of excitability in schizophrenic patients.
Collapse
Affiliation(s)
- Olga Fedorenko
- Department of Physiology, University of Tuebingen, Gmelinstr. 5, 72076 Tuebingen, Germany
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Klaus F, Gehring EM, Zürn A, Laufer J, Lindner R, Strutz-Seebohm N, Tavaré JM, Rothstein JD, Boehmer C, Palmada M, Gruner I, Lang UE, Seebohm G, Lang F. Regulation of the Na+-coupled glutamate transporter EAAT3 by PIKfyve. Neurochem Int 2009; 54:372-7. [DOI: 10.1016/j.neuint.2009.01.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
|
36
|
Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A. Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 2009; 34:1578-89. [PMID: 19078949 PMCID: PMC3400972 DOI: 10.1038/npp.2008.215] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Glutamatergic dysfunction is increasingly implicated in the pathophysiology of schizophrenia. Current models postulate that dysfunction of glutamate and its receptors underlie many of the symptoms in this disease. However, the mechanisms involved are not well understood. Although elucidating the role for glutamate transporters in the disease has been limited by the absence of pharmacological tools that selectively target the transporter, we recently showed that glial glutamate and aspartate transporter (GLAST; excitatory amino-acid transporter 1) mutant mice exhibit abnormalities on behavioral measures thought to model the positive symptoms of schizophrenia, some of which were rescued by treatment with either haloperidol or the mGlu2/3 agonist, LY379268 the mGlu2/3 agonist, LY379268. To further determine the role of GLAST in schizophrenia-related behaviors we tested GLAST mutant mice on a series of behavioral paradigms associated with the negative (social withdrawal, anhedonia), sensorimotor gating (prepulse inhibition of startle), and executive/cognitive (discrimination learning, extinction) symptoms of schizophrenia. GLAST knockout (KO) mice showed poor nesting behavior and abnormal sociability, whereas KO and heterozygous (HET) both demonstrated lesser preference for a novel social stimulus compared to wild-type littermate controls. GLAST KO, but not HET, had a significantly reduced acoustic startle response, but no significant deficit in prepulse inhibition of startle. GLAST KO and HET showed normal sucrose preference. In an instrumental visual discrimination task, KO showed impaired learning. By contrast, acquisition and extinction of a simple instrumental response was normal. The mGlu2/3 agonist, LY379268, failed to rescue the discrimination impairment in KO mice. These findings demonstrate that gene deletion of GLAST produces select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia.
Collapse
Affiliation(s)
- Rose-Marie Karlsson
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, 10-Center Drive, 10 Room 1E-5330, Bethesda, MD 20892, USA.
| | - Kohichi Tanaka
- Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Lisa M Saksida
- Department of Experimental Psychology, University of Cambridge, Cambridge, UK,The Medical Research Council and Wellcome Trust Behavioral and Clinical Neuroscience Institute, Cambridge, UK
| | - Timothy J Bussey
- Department of Experimental Psychology, University of Cambridge, Cambridge, UK,The Medical Research Council and Wellcome Trust Behavioral and Clinical Neuroscience Institute, Cambridge, UK
| | - Markus Heilig
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA,Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Andrew Holmes
- Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Rockville, MD, USA
| |
Collapse
|
|
37
|
Association analysis of the glutamic acid decarboxylase 2 and the glutamine synthetase genes (GAD2, GLUL) with schizophrenia. Psychiatr Genet 2009; 19:6-13. [DOI: 10.1097/ypg.0b013e328311875d] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
38
|
Sodhi M, Wood KH, Meador-Woodruff J. Role of glutamate in schizophrenia: integrating excitatory avenues of research. Expert Rev Neurother 2008; 8:1389-406. [PMID: 18759551 DOI: 10.1586/14737175.8.9.1389] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Schizophrenia is a debilitating lifelong disorder affecting up to 1% of the population worldwide, producing significant financial and emotional hardship for patients and their families. As yet, the causes of schizophrenia and the mechanism of action of antipsychotic drugs are unknown, and many patients do not respond well to currently available medications. Attempts to find risk factors for the disorder using epidemiological methods have shown that schizophrenia is highly heritable, and path analyses predict that the disorder is caused by several genes in combination with nongenetic factors. Therefore, intensive research efforts have been made to identify genes creating vulnerability to schizophrenia and also genes predicting response to treatment. Interactions of the glutamatergic system with dopaminergic and serotonergic circuitry are crucial for normal brain function, and their disruption may be a mechanism by which the pathophysiology of schizophrenia is manifest. Genes within the glutamatergic system are therefore strong candidates for investigation, and these include the glutamate receptor genes in addition to genes encoding neuregulin, dysbindin, D-amino acid oxidase and G72/G30. These genetic studies could eventually reveal new targets for antipsychotic drug treatment, which currently focuses on inhibition of the dopaminergic system. However, a recent breakthrough indicates clinical efficacy of a drug stimulating the metabotropic glutamate receptor II, LY2140023, which has improved efficacy for negative and cognitive symptoms of schizophrenia. Studies of larger patient samples are required to consolidate these data. Further investigation of glutamatergic targets is likely to reinvigorate antipsychotic drug development.
Collapse
Affiliation(s)
- Monsheel Sodhi
- Department of Psychiatry & Behavioral Neurobiology, University of Alabama at Birmingham, 1720 7th Avenue Sth, Rm 590C CIRC, Birmingham, AL 35294, USA.
| | | | | |
Collapse
|
|
39
|
Deng X, Sagata N, Takeuchi N, Tanaka M, Ninomiya H, Iwata N, Ozaki N, Shibata H, Fukumaki Y. Association study of polymorphisms in the neutral amino acid transporter genes SLC1A4, SLC1A5 and the glycine transporter genes SLC6A5, SLC6A9 with schizophrenia. BMC Psychiatry 2008; 8:58. [PMID: 18638388 PMCID: PMC2491607 DOI: 10.1186/1471-244x-8-58] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2007] [Accepted: 07/18/2008] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission. We report here association studies of schizophrenia with SLC1A4, SLC1A5 encoding neutral amino acid transporters ASCT1, ASCT2, and SLC6A5, SLC6A9 encoding glycine transporters GLYT2, GLYT1, respectively. METHODS We initially tested the association of 21 single nucleotide polymorphisms (SNPs) distributed in the four gene regions with schizophrenia using 100 Japanese cases-control pairs and examined allele, genotype and haplotype association with schizophrenia. The observed nominal significance were examined in the full-size samples (400 cases and 420 controls). RESULTS We observed nominally significant single-marker associations with schizophrenia in SNP2 (P = 0.021) and SNP3 (P = 0.029) of SLC1A4, SNP1 (P = 0.009) and SNP2 (P = 0.022) of SLC6A5. We also observed nominally significant haplotype associations with schizophrenia in the combinations of SNP2-SNP7 (P = 0.037) of SLC1A4 and SNP1-SNP4 (P = 0.043) of SLC6A5. We examined all of the nominal significance in the Full-size Sample Set, except one haplotype with insufficient LD. The significant association of SNP1 of SLC6A5 with schizophrenia was confirmed in the Full-size Sample Set (P = 0.018). CONCLUSION We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC6A5, whereas SLC1A4, SLC1A5 and SLC6A9 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.
Collapse
Affiliation(s)
- Xiangdong Deng
- Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
| | - Noriaki Sagata
- Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Naoko Takeuchi
- Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Masami Tanaka
- Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Hideaki Ninomiya
- Fukuoka Prefectural Dazaifu Hospital Psychiatric Center, Dazaifu, Fukuoka, Japan
| | - Nakao Iwata
- Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Norio Ozaki
- Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Hiroki Shibata
- Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Yasuyuki Fukumaki
- Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| |
Collapse
|
|
40
|
Lang UE, Puls I, Muller DJ, Strutz-Seebohm N, Gallinat J. Molecular mechanisms of schizophrenia. Cell Physiol Biochem 2007; 20:687-702. [PMID: 17982252 DOI: 10.1159/000110430] [Citation(s) in RCA: 183] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2007] [Indexed: 12/11/2022] Open
Abstract
Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.
Collapse
Affiliation(s)
- Undine E Lang
- Department of Psychiatry, Charité University Medicine Berlin, Campus Mitte, Berlin (Germany).
| | | | | | | | | |
Collapse
|