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

Clinical genetic studies have implicated neuregulin-1 [NRG1] as a leading susceptibility gene for schizophrenia. NRG1 is known to play a significant role in the developing brain, which is consistent with the prevailing neurodevelopmental model of schizophrenia. Thus, the emotional and social phenotype of adult mice with heterozygous 'knockout' of transmembrane [TM]-domain NRG1 was examined further in both sexes. Emotional/anxiety-related behaviour was assessed using the elevated plus-maze and the light-dark test. Social behaviour was examined in terms of dyadic interactions between NRG1 mutants and an unfamiliar C57BL6 conspecific in a novel environment. There was no effect of NRG1 genotype on performance in either test of emotionality/anxiety. However, previous reports of hyperactivity in NRG1 mutants were confirmed in both paradigms. In the test of social interaction, aggressive following was increased in NRG1 mutants of both sexes, together with an increase in walkovers in female mutants. These findings elaborate the specificity of the NRG1 phenotype for the social rather than the emotional/anxiety-related domain. They indicate that NRG1 is involved in the regulation of reciprocal social interaction behaviour and thus suggest a putative role for NRG1 in a schizophrenia-related endophenotype.
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PMID:Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous 'knockout' of the schizophrenia risk gene neuregulin-1. 1798 Apr 71

This overview presents a hypothesis to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. In schizophrenia, a glutamatergic hypofunction is discussed to be crucially involved in dopaminergic dysfunction. This view is supported by findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction is mediated by NMDA (N-methyl-D-aspartate) receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYN-A). KYN-A also blocks the nicotinergic acetycholine receptor, i.e. increased KYN-A levels can explain psychotic symptoms and cognitive deterioration. KYN-A levels are described to be higher in the CSF and in critical CNS regions of schizophrenics. Another line of evidence suggests that of the immune system in schizophrenic patients is characterized by an imbalance between the type-1 and the type-2 immune responses with a partial inhibition of the type-1 response, while the type-2 response is relatively over-activated. This immune constellation is associated with the inhibition of the enzyme indoleamine 2,3-dioxygenase (IDO), because type-2 cytokines are potent inhibitors of IDO. Due to the inhibition of IDO, tryptophan is predominantly metabolized by tryptophan 2,3-dioxygenase (TDO), which is located in astrocytes, but not in microglia cells. As indicated by increased levels of S100B, astrocytes are activated in schizophrenia. On the other hand, the kynurenine metabolism in astrocytes is restricted to the dead-end arm of KYN-A production. Accordingly, an increased TDO activity and an accumulation of KYN-A in the CNS of schizophrenics have been described. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g. the use of antiinflammatory cyclooxygenase-2 inhibitors, which also are able to directly decrease KYN-A, are discussed.
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PMID:The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. 1798 3

Susceptibility to complex disease appears to be partly mediated by heritable differences in gene expression. Where cis-acting effects on a gene's expression influence disease susceptibility, other genes containing polymorphism with a trans-acting effect on expression of that gene may also be expected to modulate risk. Use of the expression of an identified disease gene as an endophenotype for quantitative linkage analysis may therefore provide a powerful method for mapping loci that modulate disease susceptibility. We performed genome-wide linkage analysis on expression of dystrobrevin binding protein 1 (DTNBP1), a well-supported susceptibility gene for schizophrenia, in large CEPH pedigrees. We observed genome-wide significant evidence for linkage at the DTNBP1 locus on chromosome 6p22, and demonstrated that this reflects variable cis-acting effects on DTNBP1 expression. In addition, we observed genome-wide suggestive evidence for linkage of DTNBP1 expression to chromosome 8p, suggesting a locus that exerts a trans-acting effect on DTNBP1 expression. The region of linkage to DTNBP1 expression on chromosome 8 is contiguous with linkage findings based upon the clinical schizophrenia phenotype, and contains another well-supported schizophrenia susceptibility gene, neuregulin-1 (NRG1). Our data provide complementary evidence for chromosome 8p as a susceptibility locus for schizophrenia, and suggest that genetic variation within this region may influence risk, at least in part, through effects on DTNBP1 expression.
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PMID:Cis- and trans- loci influence expression of the schizophrenia susceptibility gene DTNBP1. 1818 43

Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and ErbB4 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53 kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180 kDa. PFC cytoplasmic 53 kDa NRG1 protein levels were significantly increased (approximately 20%) in schizophrenic patients relative to each of the other subject groups. We also detected diagnostic effects on PFC cytoplasmic full-length (180 kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (approximately 30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60 kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21 kDa/180 kDa and 55 kDa/180 kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4.
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PMID:Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. 1824 64

Animal data suggest that the gene neuregulin-1 (NRG1) is involved in neuronal myelination. A haplotype (deCODE) in the 5' end region of the gene was described to double the risk for schizophrenia in an Icelandic population (Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T.T., Hjaltason, O., Birgisdottir, B., Jonsson, H., Gudnadottir, V.G., Gudmundsdottir, E., Bjornsson, A., Ingvarsson, B., Ingason, A., Sigfusson, S., Hardardottir, H., Harvey, R.P., Lai, D., Zhou, M., Brunner, D., Mutel, V., Gonzalo, A., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M.L., Gurney, M.E., Kong, A., Gulcher, J.R., Petursson, H., Stefansson, K. 2002. Neuregulin-1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877-892). Of note, there is now increasing evidence of disturbed myelination in this illness--particularly in subcortical frontal lobe white matter (Konrad, A., Winterer, G. 2008. Disturbed structural connectivity in schizophrenia--primary factor in pathology or epiphenomenon? Schiz. Bull. [Electronic publication ahead of print]). Therefore, we investigated with diffusion tensor imaging (DTI) the impact of a tagging single nucleotide polymorphism (SNP) from the deCODE haplotype, i.e., SNP8NRG221533, on fractional anisotropy (FA), which reflects structural integrity of white matter. SNP8NRG221533 was selected because it gave the single best uncorrected association with schizophrenia in the original report by Stefansson et al. (Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T.T., Hjaltason, O., Birgisdottir, B., Jonsson, H., Gudnadottir, V.G., Gudmundsdottir, E., Bjornsson, A., Ingvarsson, B., Ingason, A., Sigfusson, S., Hardardottir, H., Harvey, R.P., Lai, D., Zhou, M., Brunner, D., Mutel, V., Gonzalo, A., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M.L., Gurney, M.E., Kong, A., Gulcher, J.R., Petursson, H., Stefansson, K. 2002. Neuregulin-1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877-892). As predicted, we found medial frontal FA to be significantly associated with this NRG1 gene variation. Using voxel-based morphometry (VBM), we could largely exclude the possibility that this genotype effect is indirectly caused by genotype-dependent effects on brain volume. This is the first demonstration that SNP8NRG221533 of the NRG1 gene affects medial frontal white matter microstructure in humans. As the degree of neuronal myelination contributes to structural integrity, our finding further supports a potential role of NRG1 in neuronal myelination in the human brain. By extension, our findings suggest that SNP8NRG221533 may contribute to the risk for the complex polygenic illness schizophrenia via its impact on myelination in frontal lobe white matter.
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PMID:Association of 5' end neuregulin-1 (NRG1) gene variation with subcortical medial frontal microstructure in humans. 1825 17

The neuregulin-1 (NRG1) gene on chromosome 8p has been suggested as a potential susceptibility gene for schizophrenia. The exact way in which genetic variation in NRG1 might impact on this susceptibility for the disorder is a focus of current research. The present study aimed at investigating the possible relationship between a putative NRG1 at-risk haplotype (HAP(ICE)) and hippocampal volumes in schizophrenic patients and their healthy first-degree relatives. We genotyped 30 schizophrenic patients and 52 non-affected family members with regard to the presence or absence of the NRG1 haplotype HAP(ICE). Structural magnetic resonance imaging was used to determine hippocampal brain volumes in the same subjects. Patients and relatives carrying haplotype HAP(ICE) both had smaller relative hippocampal volumes as compared to patients or relatives who did not carry this haplotype. These findings provide first direct evidence for a link between NRG1 genetic variation and hippocampal volume reductions in schizophrenic patients and non-affected relatives. This preliminary evidence may help to guide further research into the pathophysiological pathways that underlie this genetic susceptibility for schizophrenia.
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PMID:Neuregulin-1 haplotype HAP(ICE) is associated with lower hippocampal volumes in schizophrenic patients and in non-affected family members. 1829 20

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.
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PMID:Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. 1866 43

Synaptic strengthening produced by epileptiform activity may contribute to seizure progression and cognitive impairment in epilepsy. Agents that limit this form of plasticity may have therapeutic benefit. Neuregulin is an endogenous growth factor that is released at synapses in an activity dependent manner and can suppress long term potentiation (LTP). Alterations in neuregulin signaling have been associated with schizophrenia. A role for neuregulin in epilepsy has not been explored. We used field potential recordings to examine the role of neuregulin in regulating synaptic strengthening following epileptiform activity in hippocampal slices. Neuregulin had no effect on basal synaptic transmission, isolated NMDA field potentials or GABAergic inhibition on CA1 pyramidal neurons. However, it reversed LTP at CA1 synapses. Brief exposure to 10 mM potassium chloride produced epileptiform bursting and potentiation of CA1 synapses and suppressed the subsequent induction of LTP. Neuregulin reversed high K(+)-induced synaptic strengthening, enabling LTP induction after neuregulin washout. In this manner neuregulin preserved the dynamic range of synaptic responses and plasticity after epileptiform activity. These results indicate that LTP and high K(+)-induced synaptic strengthening share a common neuregulin-sensitive mechanism. By opposing synaptic strengthening caused by epileptiform activity, we suggest that neuregulin may reduce the generation and spread of seizures as well as memory deficits associated with epilepsy.
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PMID:Neuregulin blocks synaptic strengthening after epileptiform activity in the rat hippocampus. 1838

Neuregulin-1 (Nrg-1)(1) gene has been considered as a schizophrenia susceptibility gene. In order to observe the association of Nrg-1 gene with schizophrenia, the study was designed to investigate the effect of anti-psychotic treatment on the Nrg-1 mRNA expression in peripheral blood lymphocytes of the patients with a diagnosis of schizophrenia. The Nrg-1 mRNA expression in peripheral blood lymphocytes (PBLs) was measured by using semi-quantitative RT-PCR in 31 first-onset schizophrenia patients, 16 sibling controls and 31 no-sibship controls. Results showed that Nrg-1 mRNA expression in PBLs of patients was lower than that in other two control groups (F=6.722, P=0.002). However, as follow-up time extended, from the second week, Nrg-1 mRNA expression of PBLs in antipsychotic treated patients gradually increased and has obvious statistical significance compared the efficacy of taking anti-psychotic before and after therapy. These results demonstrated that Nrg-1 gene has association with schizophrenia. It is possible to select Nrg-1 mRNA expression of PBLs in schizophrenia patients as a potential therapeutic marker.
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PMID:Explorative study on the expression of neuregulin-1 gene in peripheral blood of schizophrenia. 1845 3

Schizophrenia is characterized by a great heterogeneity of symptoms and functional deficits, especially of cognition. Different phenotypes are thought to result from the interaction of genetic predisposition and environmental factors. Pathophysiological models range from the dopamine and glutamate hypotheses to the hypothesis of free radicals and the hypotheses of neurodevelopment as opposed to neurodegeneration. In addition to the neurobiological approaches, linkage studies and subsequent finemappings deliver evidence with regard to genes potentially involved in schizophrenia. The most important candidate genes, such as dysbindin (DTNBP1), neuregulin (NRG1) and DISC-1 (disrupted-in schizophrenia-1), are thought to influence neurotransmission, as well as the development and maintenance of the structure of neuronal networks. The list of potential candidates includes numerous other genes as well. In conclusion, multiple genetic, neurobiological, and exogenous factors are assumed to interact in the pathogenesis of schizophrenia.
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PMID:[Genetic findings in schizophrenia]. 1847


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