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)

Postmortem studies, using various methods and directed at several molecular targets, have provided increasing evidence that glutamatergic neurotransmission is affected in schizophrenia. The bulk of the data are in the hippocampus, wherein there is reduced expression of one or more subunits for all three ionotropic receptors (NMDA, AMPA, and kainate). Presynaptic glutamatergic markers, notably the vesicular glutamate transporter VGLUT1, may also be decreased in schizophrenia, especially in older subjects. CA1 appears less affected than other subfields, and the decrements may be greater in the left than in the right hippocampus. The recently described susceptibility genes for schizophrenia all act upon glutamatergic synaptic transmission, which may, therefore, be part of the core pathophysiology of the disorder.
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PMID:Glutamate receptors and transporters in the hippocampus in schizophrenia. 1468 37

Dopamine neurons have been suggested to use glutamate as a cotransmitter. To identify the basis of such a phenotype, we have examined the expression of the three recently identified vesicular glutamate transporters (VGLUT1-3) in postnatal rat dopamine neurons in culture. We found that the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3. In comparison, serotonin neurons express only VGLUT3. Single-cell RT-PCR experiments confirmed the presence of VGLUT2 mRNA in dopamine neurons. Arguing for phenotypic heterogeneity among axon terminals, we find that only a proportion of terminals established by dopamine neurons are VGLUT2-positive. Taken together, our results provide a basis for the ability of dopamine neurons to release glutamate as a cotransmitter. A detailed analysis of the conditions under which DA neurons gain or loose a glutamatergic phenotype may provide novel insight into pathophysiological processes that underlie diseases such as schizophrenia, Parkinson's disease and drug dependence.
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PMID:Dopamine neurons in culture express VGLUT2 explaining their capacity to release glutamate at synapses in addition to dopamine. 1500 40

Converging research efforts over the last 4 decades have established beyond a doubt that many, if not most, neurons release more than 1 neurotransmitter. Although much attention has been paid to the co-release of small-molecule neurotransmitters with neuropeptides, a number of examples of co-release of 2 small-molecule neurotransmitters have now been described. It has been suggested recently that monoamine neurons use glutamate as a co-transmitter. First, both serotonin (5-HT) and dopamine (DA) neurons in culture establish functional glutamatergic synapses in addition to classic terminals that release 5-HT or DA. Second, immunocytochemical work has provided evidence for the presence of neurotransmitter pools of glutamate in DA, 5-HT and noradrenergic neurons. Third, the recent cloning of 3 vesicular glutamate transporters (VGLUT1-3) has led to the discovery that noradrenergic neurons contain VGLUT2 mRNA, whereas 5-HT neurons contain VGLUT3 mRNA. Finally, although VGLUT2 mRNA does not appear to be abundant in DA neurons in the adult brain, DA neurons cultured from neonatal animals express VGLUT2, suggesting that these neurons may have the capacity to express this protein under specific conditions. Taken together with recent work describing the capacity of neurons to change neurotransmitter phenotype during development or in an activity-dependent manner, the finding of glutamate co-transmission in monoamine neurons may lead to significant revisions of current physiologic models of monoamine neuron function. In addition, the possible role of glutamate co-release in physiopathologic models of diseases that implicate central monoamine pathways, such as schizophrenia, must now be seriously considered.
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PMID:Glutamate co-transmission as an emerging concept in monoamine neuron function. 1530 46

Synaptic protein gene expression is altered in schizophrenia. In the hippocampal formation there may be particular involvement of glutamatergic neurons and their synapses, but overall the profile remains unclear. In this in situ hybridization histochemistry (ISHH) study, we examined four informative synaptic protein transcripts: vesicular glutamate transporter (VGLUT) 1, VGLUT2, complexin I, and complexin II, in dorsolateral prefrontal cortex (DPFC), superior temporal cortex (STC), and hippocampal formation, in 13 subjects with schizophrenia and 18 controls. In these areas, VGLUT1 and complexin II are expressed primarily by excitatory neurons, whereas complexin I is mainly expressed by inhibitory neurons. In schizophrenia, VGLUT1 mRNA was decreased in hippocampal formation and DPFC, complexin II mRNA was reduced in DPFC and STC, and complexin I mRNA decreased in STC. Hippocampal VGLUT1 mRNA declined with age selectively in the schizophrenia group. VGLUT2 mRNA was not quantifiable due to its low level. The data provide additional evidence for a synaptic pathology in schizophrenia, in terms of a reduced expression of three synaptic protein genes. In the hippocampus, the loss of VGLUT1 mRNA supports data indicating that glutamatergic presynaptic deficits are prominent, whereas the pattern of results in temporal and frontal cortex suggests broadly similar changes may affect inhibitory and excitatory neurons. The impairment of synaptic transmission implied by the synaptic protein reductions may contribute to the dysfunction of cortical neural circuits that characterises the disorder.
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PMID:Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons. 1565 59

Delineating the molecular basis of synapse development is crucial for understanding brain function. Cocultures of neurons with transfected fibroblasts have demonstrated the synapse-promoting activity of candidate molecules. Here, we performed an unbiased expression screen for synaptogenic proteins in the coculture assay using custom-made cDNA libraries. Reisolation of NGL-3/LRRC4B and neuroligin-2 accounts for a minority of positive clones, indicating that current understanding of mammalian synaptogenic proteins is incomplete. We identify LRRTM1 as a transmembrane protein that induces presynaptic differentiation in contacting axons. All four LRRTM family members exhibit synaptogenic activity, LRRTMs localize to excitatory synapses, and artificially induced clustering of LRRTMs mediates postsynaptic differentiation. We generate LRRTM1(-/-) mice and reveal altered distribution of the vesicular glutamate transporter VGLUT1, confirming an in vivo synaptic function. These results suggest a prevalence of LRR domain proteins in trans-synaptic signaling and provide a cellular basis for the reported linkage of LRRTM1 to handedness and schizophrenia.
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PMID:An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. 1928 59

Dysregulation of glutamate neurotransmission is implicated in the pathphysiology of schizophrenia. Vesicular glutamate transporters (VGLUTs) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. Abnormal VGLUT1 expression has been linked to schizophrenia in postmortem brain studies. The purpose of this study was to investigate the involvement of the human VGLUT1 in the susceptibility to schizophrenia. In this study, we searched for genetic variants in the putative core promoter region and 12 exons (including UTR ends) of the VGLUT1 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=376) and non-psychotic controls (n=368) from Taiwan, and conducted a case-control association study. We identified two common SNPs (g.-248G>C (ss159695612) and c.2697C>A (rs1043558)) in the VGLUT1 gene. No differences in the allele and genotype frequencies were detected between the patients and control subjects. Besides, we identified eight patient-specific rare variants in 16 out of 376 patients, including two variants (g.-296A>G (ss159695611) and g.-32Cv>T (ss159695613)) at the core promoter region and 5'UTR, two missense variants (L516M (ss159695617) and P551S (ss159695618)) and three silent variants (E24E (ss159695614), L118L (ss159695615), and P133P (ss159695616)) at protein-coding regions, and one variant (c.2201G>A (ss159695619)) at the 3'UTR. No rare variants were found in 368 control subjects (4.3% versus 0, P=1.5x10(-5)). Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutation hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.
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PMID:Resequencing and association study of vesicular glutamate transporter 1 gene (VGLUT1) with schizophrenia. 1972 May 1

Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Studies have demonstrated reductions in synapsin II mRNA and protein in medial prefrontal cortical post-mortem samples from patients with schizophrenia, genetic associations between synapsin II and schizophrenia, and synapsin II protein regulation by dopamine receptor activation. Collectively, this research indicates a relationship between synapsin II dysregulation and schizophrenia; however, it remains unknown whether perturbations in synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with selective knock-down of synapsin II in the medial prefrontal cortex. After continuous infusion of synapsin II antisense sequences, animals were examined for the presence of schizophrenic-like behavioral phenotypes and assessed on the response to clinically relevant antipsychotic drugs. Our results indicate that rats with selective reductions in medial prefrontal cortical synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), reduced social behavior, and hyperlocomotion, which are corrected by the atypical antipsychotic drug olanzapine. Additionally, synapsin II knock-down disrupts serial search efficiency. These behavioral changes are accompanied by reductions in vesicular neurotransmitter transporter protein concentrations for glutamate (VGLUT1 and VGLUT2) and GABA (VGAT), without affecting dopamine (VMAT2). These results implicate a causal role for decreased synapsin II in the medial prefrontal cortex in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that synapsin II may potentially serve as a novel therapeutic target for this disorder.
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PMID:Medial prefrontal cortical synapsin II knock-down induces behavioral abnormalities in the rat: examining synapsin II in the pathophysiology of schizophrenia. 2168 7

Glutamate is the main excitatory neurotransmitter in the central nervous system. A hypoglutamatergic state is believed to play an important role in the pathophysiology of schizophrenia. The release of glutamate in the brain is modulated by a class of vesicular glutamate transporters, VGLUT1-3. Among them, VGLUT1 represents the isoform predominantly expressed in the neocortex and hippocampus. Here we investigated the potential involvement of VGLUT1 deficiency in generating schizophrenia-like abnormalities by testing mice with diminished expression of VGLUT1 in several behavioural tests relevant for schizophrenia. We found behavioural alterations in these mice resembling correlates of schizophrenia, such as working- and social memory impairments and deficits in prepulse inhibition (PPI) of the acoustic startle reflex (ASR), but normal locomotor behaviour under basal conditions. Our data may be important for a better understanding of the contribution of reduced VGLUT1-mediated presynaptic glutamatergic neurotransmission in the generation of several behavioural abnormalities associated with schizophrenia.
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PMID:Sensorimotor gating, working and social memory deficits in mice with reduced expression of the vesicular glutamate transporter VGLUT1. 2219 96

Glutamate transporters facilitate the buffering, clearance and cycling of glutamate and play an important role in maintaining synaptic and extrasynaptic glutamate levels. Alterations in glutamate transporter expression may lead to abnormal glutamate neurotransmission contributing to the pathophysiology of schizophrenia. In addition, alterations in the architecture of the superior temporal gyrus and hippocampus have been implicated in this illness, suggesting that synapses in these regions may be remodeled from a lifetime of severe mental illness and antipsychotic treatment. Thus, we hypothesize that glutamate neurotransmission may be abnormal in the superior temporal gyrus and hippocampus in schizophrenia. To test this hypothesis, we examined protein expression of excitatory amino acid transporter 1-3 and vesicular glutamate transporter 1 and 2 in subjects with schizophrenia (n=23) and a comparison group (n=27). We found decreased expression of EAAT1 and EAAT2 protein in the superior temporal gyrus, and decreased EAAT2 protein in the hippocampus in schizophrenia. We didn't find any changes in expression of the neuronal transporter EAAT3 or the presynaptic vesicular glutamate transporters VGLUT1-2. In addition, we did not detect an effect of antipsychotic medication on expression of EAAT1 and EAAT2 proteins in the temporal association cortex or hippocampus in rats treated with haloperidol for 9 months. Our findings suggest that buffering and reuptake, but not presynaptic release, of glutamate is altered in glutamate synapses in the temporal lobe in schizophrenia.
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PMID:Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia. 2335 50

Schizophrenia is a severe psychiatric disorder with an estimate prevalence of 0.3-0.7%. Studies on family aggregation showed a higher incidence of disease among family members of affected people. This observation lead to formulate the hypothesis that schizophrenia could be inheritable, but twin studies have shown a concordance of disease between monozygotic twins only of 50%, indicating the concomitant role of environmental factors in the pathogenesis of schizophrenia. Researches in molecular biology field have allowed the identification of genes that confer susceptibility to schizophrenia on chromosomes 1, 2, 3, 5, 6, 8, 10, 11, 13, 14, 20 and 22. Epigenetic modifications of gene expression, that not involve the primary DNA sequence, may also predispose to schizophrenia, in particular the methylation of genes involved in neurotransmission (RELN, GAD1, MARLIN-1, and NR3B GRIA2, VGLUT1 and 2, 5HT2a, COMT and BDNF), the histone modifications and the action of non-coding RNAs. This review deals with the results of a bibliographic retrieval on PubMed, carried out, using the key words: schizophrenia, genetics, epigenetics. From the epitomized results it can be derived that schizophrenia seems to be a multifactorial disease. Environmental factors, that can cause epigenetic modifications, are important in its pathogenesis, acting on a biological inheritable vulnerability.
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PMID:[Genetics and epigenetics of schizophrenia]. 2404 31


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