Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment

Wilmsdorff, Martina von; Blaich, Carolin; Zink, Mathias; Treutlein, Jens; Bauer, Manfred; Schulze, Thomas G.; Schneider‐Axmann, Thomas; Gruber, Oliver; Rietschel, Marcella; Schmitt, Andrea; Falkai, Peter

doi:10.3109/15622975.2011.645877

Cited by 16 publications

(13 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Levels of EAAT1 mRNA have been reported as higher in the cerebellar vermis[ 113 ], AnCg[ 114 ], thalamus[ 115 ] and prefrontal cortex[ 116 ] of subjects with schizophrenia. In comparison, other studies have found no changes in EAAT1 expression in the DLPFC[ 76 , 114 ] or primary visual cortex[ 76 ] of subjects with schizophrenia.…”

Section: Eaats In Psychiatric Illnessmentioning

confidence: 99%

Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

Parkin

Udawela

Gibbons

et al. 2018

WJP

101

View full text Add to dashboard Cite

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.

show abstract

Section: Eaats In Psychiatric Illnessmentioning

confidence: 99%

Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

Parkin

Udawela

Gibbons

et al. 2018

WJP

101

View full text Add to dashboard Cite

show abstract

“…By comparing gene expression data from human cohorts with those from haloperidol-treated versus control monkeys, both by microarray and in situ hybridization analyses, they were able to highlight gene expression changes in schizophrenics unrelated to APD treatment. Since then, a number of postmortem investigations have addressed the potential impact of APD based on the analysis of chronically treated nonhuman primates (see in particular work from the group of D. Lewis at Pittsburgh, e.g., [14][15][16]) or rodents (e.g., [17][18][19]).…”

Section: Introductionmentioning

confidence: 99%

Proteome effects of antipsychotic drugs: Learning from preclinical models

Carboni

Domenici

2015

Proteomics Clinical Apps

View full text Add to dashboard Cite

Proteome-wide expression analyses are performed in the brain of schizophrenia patients to understand the biological basis of the disease and discover molecular paths for new clinical interventions. A major issue with postmortem analysis is the lack of tools to discern molecular modulation related to the disease from dysregulation due to medications. We review available proteome-wide analysis of antipsychotic treatment in rodents, highlighting shared dysregulated pathways that may contribute to an extended view of molecular processes underlying their pharmacological activity. Fourteen proteomic studies conducted with typical and atypical antipsychotic treatments were examined; hypothesis-based approaches are also briefly discussed. Treatment with antipsychotics mainly affects proteins belonging to metabolic pathways involved in energy generation, both in glycolytic and oxidative phosphorylation pathways, suggesting antipsychotics-induced impairments in metabolism. Nevertheless, schizophrenic patients show impaired glucose metabolism and mitochondrial dysfunctions independent of therapy. Other antipsychotics-induced changes shared by different studies implicate cytoskeletal and synaptic function proteins. The mechanism can be related to the reorganization of dendritic spines resulting from neural plasticity events induced by treatments affecting neurotransmitter circuitry. However, metabolic and plasticity pathways activated by antipsychotics can also play an authentic role in the etiopathological basis of schizophrenia.

show abstract

“…Furthermore, SLC1A2 and SLC1A3 protein were found to be reduced in mGluR2-/-and mGluR3-/-mice, which might be lead to, altered synaptic glutamate levels . Recent literature also indicates altered expression of glutamate transporters-SLC1A1, SLC1A2, SLC1A3, and SLC1A4 resulting in the abnormal glutamate neurotransmission which have all been implicated in several pathological conditions including schizophrenia [Bianchi et al, 2001;Smith et al, 2001;Weis et al, 2007;Bauer et al, 2010;Shan et al, 2013;Wilmsdorff et al, 2013]. Thus, genetic variations in these genes also need to be studied to assess their potential to influence the disease development and therapeutic outcome.…”

Section: Introductionmentioning

confidence: 99%

Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness

Kaur

Jajodia

Grover

et al. 2014

American J of Med Genetics Pt B

View full text Add to dashboard Cite

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.

show abstract

Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment

Abstract: Increased SLC1A3 expression indicates facilitated transport and may result in reduced glutamate neurotransmission. Decreased SLC1A6 expression in NRG1 risk variant may be an adaptive effect to restore glutamate signalling, but treatment effects cannot be excluded.

Cited by 16 publications

References 42 publications

Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

Proteome effects of antipsychotic drugs: Learning from preclinical models

Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness

Contact Info

Product

Resources

About