Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because abnormalities of glutamatergic neurotransmission in psychiatric illness are likely not limited to glutamate receptor expression, we investigated expression of excitatory amino acid transporters (EAATs) in the striatum. The EAATs, normally expressed in both glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4), have previously been implicated in Huntington's disease, amyotrophic lateral sclerosis, and schizophrenia. In this study, we investigated striatal expression of transcripts encoding EAATs in tissue from mood disordered and schizophrenic subjects. With probes designed for the human EAAT1, EAAT2, EAAT3, and EAAT4 transcripts, we performed in situ hybridization and detected decreased expression of EAAT3 and EAAT4 transcripts in the striatum in bipolar disorder. We also detected decreased EAAT3 transcript expression in schizophrenia and decreased EAAT4 transcript expression in major depressive disorder. These results suggest that changes in striatal transporter mRNA expression are restricted to neuronal EAATs and extend the body of evidence implicating abnormal glutamatergic neurotransmission in schizophrenia and mood disorders.
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PMID:Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. 1185 Jan 51

Abnormalities of the glutamatergic system in schizophrenia have been identified in numerous studies, but little is known about the role of glutamate transporters and their messenger RNA (mRNA) expression. In addition, the abundances of the two major isoforms of human excitatory amino acid transporter 2 (EAAT2) or its rat ortholog, glutamate transporter 1, have never been compared in a quantitative manner. Using quantitative reverse transcription-polymerase chain reaction, we established that the expression of the EAAT1, EAAT2a, EAAT2b, and EAAT3 transcripts was not different in the dorsolateral prefrontal and primary visual cortices of persons with schizophrenia relative to matched controls. EAAT2a expression was about 25-fold and 10-fold higher than EAAT2b in human and rat brain, respectively. The data provided no evidence of an effect of antipsychotic medications on the mRNA expression of the glutamate transporters. However, because most of the schizophrenic subjects in the cohort had been treated with antipsychotics for many years, it is still possible that changes in transporter expression were masked by medication effects.
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PMID:Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain. 1629 66

The excitatory amino acid transporters (EAATs) are a family of plasma membrane proteins that maintain synaptic glutamate concentration by removing glutamate from the synaptic cleft. EAATs are expressed by glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4) throughout the brain. Glutamate reuptake is regulated, in part, by EAAT-interacting proteins that modulate subcellular localization and glutamate transport activity of the EAATs. Several lines of investigation support the hypothesis of glutamatergic abnormalities in schizophrenia. Previous work in our laboratory demonstrated increased expression of EAAT1 and EAAT2 transcripts in the thalamus, suggesting that alterations in synaptic glutamate levels may contribute to the pathophysiology of schizophrenia. Since EAAT-interacting proteins regulate EAAT function, directly impacting glutamatergic neurotransmission, we hypothesized that expression of EAAT-interacting proteins may also be altered in schizophrenia. Using in situ hybridization in subjects with schizophrenia and a comparison group, we detected increased expression of JWA and KIAA0302, molecules that regulate EAAT3 and EAAT4, respectively, in the thalamus in schizophrenia. In contrast, we did not find changes in the expression of transcripts for the EAAT2 and EAAT4 regulatory proteins GPS-1 and ARHGEF11. To address prior antipsychotic treatment in our schizophrenic subjects, we treated rats with haloperidol and clozapine for 4 weeks, and found changes in transcript expression of the EAAT-interacting proteins in clozapine-, but not haloperidol-, treated rats. These findings suggest that proteins associated with the regulation of glutamate reuptake may be abnormal in this illness, supporting the hypothesis of altered thalamic glutamatergic neurotransmission in schizophrenia.
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PMID:Expression of excitatory amino acid transporter interacting protein transcripts in the thalamus in schizophrenia. 1648 62

Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the glutamate receptor and transporter genes. We report here association studies of schizophrenia with three glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 encoding the glutamate transporters EAAT3, EAAT1, and EAAT4, respectively. We initially performed the screening of the total 25 single nucleotide polymorphisms (SNPs) distributed in the three gene regions using 100 out of 400 Japanese cases and 100 out of 420 Japanese controls. After controlling the false discovery rate (FDR) at level 0.05, we observed significant associations of schizophrenia with a genotype of SNP4 (rs2097837, P = 0.007) and with haplotypes of SNP2-SNP5 (P = 7.5 x 10(-5)) and SNP3-SNP5 (P = 9.0 x 10(-4)) in the SLC1A6 region. The haplotype of SNP2-SNP5 of SLC1A6 even showed marginally significant association with the disease in the full-size sample (400 cases and 420 controls, P = 0.031). We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC1A6, whereas SLC1A1 and SLC1A3 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.
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PMID:Association study of polymorphisms in the glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 with schizophrenia. 1722 39

Glutamate cycling is critically important for neurotransmission, and may be altered in schizophrenia. The excitatory amino acid transporters (EAATs) facilitate the reuptake of glutamate from the synaptic cleft and have a key role in glutamate cycling. We hypothesized that expression of the EAATs and the EAAT regulating proteins ARHGEF11, JWA, G-protein suppressor pathway 1 (GPS1), and KIAA0302 are altered in the brain in schizophrenia. To test this, we measured expression of EAAT1, EAAT2, EAAT3, and EAAT interacting proteins in postmortem tissue from the dorsolateral prefrontal and anterior cingulate cortex of patients with schizophrenia and a comparison group using in situ hybridization and Western blot analysis. We found increased EAAT1 transcripts and decreased protein expression, increased EAAT3 transcripts and protein, and elevated protein expression of both GPS1 and KIAA0302 protein. We did not find any changes in expression of EAAT2. These data indicate that proteins involved in glutamate reuptake and cycling are altered in the cortex in schizophrenia, and may provide potential targets for future treatment strategies.
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PMID:Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. 1867 70

Group II metabotropic glutamate receptors (mGluR2 and mGluR3, also called mGlu2 and mGlu3, encoded by GRM2 and GRM3, respectively) are therapeutic targets for several psychiatric disorders. GRM3 may also be a schizophrenia susceptibility gene. mGluR2-/- and mGluR3-/- mice provide the only unequivocal means to differentiate between these receptors, yet interpretation of in vivo findings may be complicated by secondary effects on expression of other genes. To address this issue, we examined the expression of NMDA receptor subunits (NR1, NR2A, NR2B) and glutamate transporters (EAAT1-3), as well as the remaining group II mGluR, in the hippocampus of mGluR2-/- and mGluR3-/- mice, compared with wild-type controls. mGluR2 mRNA was increased in mGluR3-/- mice, and vice versa. NR2A mRNA was increased in both knockout mice. EAAT1 (GLAST) mRNA and protein, and EAAT2 (GLT-1) protein, were reduced in mGluR3-/- mice, whereas EAAT3 (EAAC1) mRNA was decreased in mGluR2-/- mice. Transcripts for NR1 and NR2B were unchanged. The findings show a compensatory upregulation of the remaining group II metabotropic glutamate receptor in the knockout mice. Upregulation of NR2A expression suggests modified NMDA receptor signaling in mGluR2-/- and mGluR3-/- mice, and downregulation of glutamate transporter expression suggests a response to altered synaptic glutamate levels. The results show a mutual interplay between mGluR2 and mGluR3, and also provide a context in which to interpret behavioral and electrophysiological results in these mice.
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PMID:Altered hippocampal expression of glutamate receptors and transporters in GRM2 and GRM3 knockout mice. 1872 May 15

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.
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PMID:Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. 1907 49

Glutamatergic neurotransmission is critically involved into the pathogenesis of schizophrenic psychosis, in particular regarding cognitive and negative symptoms. The reported molecular mechanisms include increased glutamate transporter expression and antipsychotic agents such as clozapine were found able to suppress the expression of these genes. So far, the effects of the partial dopaminergic and serotonergic agonist aripiprazole on glutamatergic neurotransmission were never investigated. In a rat animal model of long-term antipsychotic treatment, we analyzed the expression of glutamate transporter genes after treatment with aripiprazole. Groups of 6 male Sprague-Dawley rats were treated for 4 weeks or 4 months with daily oral doses of 10 or 40mg aripiprazole per kg. Using semi-quantitative in situ-hybridization, we assessed the expression of pre- and post-synaptic glutamate transporter genes. Compared to control animals, differential expression levels were found in several cortical and hippocampal regions. The astroglial excitatory amino acid transporter genes EAAT1 and EAAT2 as well as the neuronal transporter EAAT3 were suppressed, while the presynaptic vesicular glutamate transporter vGluT1 was transiently induced in hippocampal subregions and EAAT4 was transiently suppressed in frontocortical areas. These transcriptional effects exerted by aripiprazole may counteract a glutamatergic deficit state and strengthen the neurotransmission of glutamate with positive consequences on cognitive and negative symptoms of schizophrenia.
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PMID:Differential expression of glutamate transporter genes after chronic oral treatment with aripiprazole in rats. 1952 31

The excitatory amino acid transporters (EAATs) are a family of molecules that are essential for regulation of synaptic glutamate levels. The EAATs may also be regulated by N-glycosylation, a posttranslational modification that is critical for many cellular functions including localization in the plasma membrane. We hypothesized that glycosylation of the EAATs is abnormal in schizophrenia. To test this hypothesis, we treated postmortem tissue from the dorsolateral prefrontal and anterior cingulate cortices of patients with schizophrenia and comparison subjects with deglycosylating enzymes. We then measured the resulting shifts in molecular weight of the EAATs using Western blot analysis to determine the mass of glycans cleaved from the transporter. We found evidence for less glycosylation of both EAAT1 and EAAT2 in schizophrenia. We did not detect N-linked glycosylation of EAAT3 in either schizophrenia or the comparison subjects in these regions. Our data suggest an abnormality of posttranslational modification of glutamate transporters in schizophrenia that suggests a decreased capacity for glutamate reuptake.
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PMID:Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. 1971 71

Abnormalities in L-glutamate signal transmission have been postulated to play a role in major mental illnesses. The glial disruption results in decreased uptake of glutamate and an elevation of extracellular glutamate levels. Elevated extracellular glutamate may cause cytotoxic damage to neurons and glia. Significant down-regulation of glial glutamate transporters, GLT1 and GLAST, in major depressive disorder has been reported. In the present study we examined the role of glial glutamate transporters in the pathogenesis of autism and schizophrenia. We generated animal models in which glutamate receptors are overstimulated by genetic down-regulation of glial glutamate transporters. Resulting mutant mice showed abnormal social interaction, increased anxiety-like behavior, and select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia. We observed enlarged amygdala and hippocampus. These mutant mice replicate many aspects of the behavioral and neuroanatomical abnormalities seen in autism and schizophrenia. Thus, these mutants are new animal models of major mental illness.
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PMID:[Role of glutamate transporters in the pathophysiology of major mental illnesses]. 1976 83


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