UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes.
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PMID:A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci. 1673 33

A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques.
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PMID:Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. 1678 99

Epidemiologic studies demonstrate significant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia and indicate their detrimental influences on brain development in this disorder. Based on these findings, animal models for schizophrenia have been established using double stranded RNA, bacterial lipopolysaccharides, hippocampal lesion, or prenatal/perinatal ischemia. Key molecules regulating such immune/inflammatory reactions are cytokines, which are also involved in brain development, regulating dopaminergic and GABAergic differentiation, and synaptic maturation. Specific members of the cytokine family, such as interleukin-1, epidermal growth factor, and neuregulin-1, are induced after infection and brain injury; therefore, certain cytokines are postulated to have a central role in the neurodevelopmental defects of schizophrenia. Recently, to test this hypothesis, a variety of cytokines were administered to rodent pups. Cytokines administered in the periphery penetrated the immature blood-brain barrier and perturbed phenotypic neural development. Among the many cytokines examined, epidermal growth factor (or potentially other ErbB1 ligands) and interleukin-1 specifically induced the most severe and persistent behavioral and cognitive abnormalities, most of which were ameliorated by antipsychotics. These animal experiments illustrate that, during early development, these cytokine activities in the periphery perturbs normal brain development and impairs later psychobehavioral and/or cognitive traits. The neurodevelopmental and behavioral consequences of prenatal/perinatal cytokine activity are compared with those of other schizophrenia models and cytokine interactions with genes are also discussed in this review.
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PMID:Recent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines. 1683 94

This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO - located in astrocytes and microglial cells - is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.
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PMID:Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. 1706 75

Causal treatment options for schizophrenia are lacking due to our restricted knowledge of its etiology and pathogenesis. However, recently three postulated disposition genes for schizophrenia have been increasingly better confirmed: dysbindin, neuregulin-1, and G(72)/DAOA genes. These genes code proteins involved in processes ranging from brain development to the maintenance of glutamatergic transmission in the mature brain. Current interpretation of neuroanatomical findings points at reminiscences of disturbed brain development and a loss of nonneuronal elements, the so-called neuropil, as a correlate of brain atrophy. This reduction in neuropil is mainly caused by synaptic elements. Biochemical findings supporting this show that besides the dopaminergic and serotonergic system, glutamatergic transmission is also disturbed in schizophrenia. All these findings fit very well with the presumed functions of the disposition genes. Hypothesis-free approaches in structural brain imaging and the combination of functional imaging with relevant gene variants open new avenues for using markers from brain imaging to improve the diagnosis of schizophrenia and judge the response to neuroleptic treatment. Despite the enormous increase in knowledge for example in genetic research, the risk variants known until now provide no contribution to early diagnosis of schizophrenia. Furthermore, pharmacogenetics is currently unable to give a clear answer as to whether a single patient is responding to treatment or not.
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PMID:[Advances in neurobiological understanding of schizophrenia. Perspectives for new therapeutic concepts]. 1707 67

The neuregulins (NRGs) play important roles in animal physiology, and their disregulation has been linked to diseases such as cancer or schizophrenia. The NRGs may be produced as transmembrane proteins (proNRGs), even though they lack an N-terminal signal sequence. This raises the question of how NRGs are sorted to the plasma membrane. It is also unclear whether in their transmembrane state, the NRGs are biologically active. During studies aimed at solving these questions, we found that deletion of the extracellular juxtamembrane region termed the linker, decreased cell surface exposure of the mutant proNRG(DeltaLinker), and caused its entrapment at the cis-Golgi. We also found that cell surface-exposed transmembrane NRG forms retain biological activity. Thus, a mutant whose cleavage is impaired but is correctly sorted to the plasma membrane activated ErbB receptors in trans and also stimulated proliferation. Because the linker is implicated in surface sorting and the regulation of the cleavage of transmembrane NRGs, our data indicate that this region exerts multiple important roles in the physiology of NRGs.
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PMID:The extracellular linker of pro-neuregulin-alpha2c is required for efficient sorting and juxtacrine function. 1710 27

Schizophrenia has long been approached from a translational perspective; however, new findings from the past decade have radically affected the dominant accounts of this illness. It is now possible to derive a consistent account of one contributing cause of schizophrenia across multiple levels of analysis, from genes to receptors, functional neuroanatomy, cognition, and symptoms. To this end, we summarize the data attributing the disorganization symptoms of schizophrenia to a failure of executive, prefrontal cortical processes. We describe the hypothesis that this failure reflects an impairment in N-methyl-D-aspartate (NMDA) glutamatergic neurotransmission, that is likely to involve both the dysregulated function of NMDA synapses, as well as the physical loss of NMDA synapses, particularly in prefrontal cortex. Dysregulation in NMDA synaptic function can be in turn attributed to polymorphisms in a variety of genes (regulator of G-protein signaling 4, dystrobrevin binding protein I, neuregulin-1, D-amino acid oxidase activator, and others) that have been linked to schizophrenia and are likely to impact NMDA-mediated synaptic neuroplasticity. Although the science of schizophrenia is not yet at a point where any domain or set of findings provides strong constraints across other levels of analysis, the further development of evidence for this chain of causation can provide increasingly strong tests of the NMDA synapse deficit theory.
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PMID:Translational and developmental perspective on N-methyl-D-aspartate synaptic deficits in schizophrenia. 1715 4

Here we overview Disrupted-in-Schizophrenia-1 (DISC1), a promising lead in studying the pathophysiology of major mental conditions. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. Different from several other susceptibility genes for schizophrenia, such as neuregulin-1 and dysbindin, there are two independent pedigrees in which genetic variations of DISC1 directly segregate with major mental conditions. This uniqueness has facilitated neurobiology of DISC1, which may hopefully lead to an important breakthrough in understanding of pathophysiology of major mental conditions. DISC1 is a multifunctional protein that plays a role in neurodevelopment and cell signaling. In autopsied brains from patients with psychosis and substance abuse, change in subcellular distribution of DISC1 is observed. DISC1 interacts with phosphodiesterase (PDE) 4B that degrades cyclic AMP (cAMP), which may be a regulatory molecule for working memory in the prefrontal cortex. Knockdown expression of DISC1 in developing cerebral cortex in mouse brains leads to changes that resemble, at least in part, the pathology found in patients with schizophrenia. These results support involvement of DISC1 in the pathophysiology of major mental conditions, including schizophrenia, in several mechanisms.
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PMID:Disrupted-in-schizophrenia-1 (DISC1): a key susceptibility factor for major mental illnesses. 1718 11

Schizophrenia is noted for the remarkably high prevalence of substance use disorders (SUDs) including nicotine (>85%), alcohol and stimulants. Mounting evidence supports the hypothesis that the endophenotype of schizophrenia involves hypofunction of a subpopulation of cortico-limbic NMDA receptors. Low doses of NMDA receptor antagonists such as ketamine replicate in normal volunteers positive, negative and cognitive symptoms of schizophrenia as well as associated physiologic abnormalities such as eye tracking and abnormal event related potentials. Genetic studies have identified putative risk genes that directly or indirectly affect NMDA receptors including D-amino acid oxidase, its modulator G72, proline oxidase, mGluR3 and neuregulin. Clinical trials have shown that agents that directly or indirectly enhance the function of the NMDA receptor at its glycine modulatory site (GMS) reduce negative symptoms and in the case of D-serine and sarcosine improve cognition and reduce positive symptoms in schizophrenic subjects receiving concurrent anti-psychotic medications. Notably, the GMS partial agonist D-cycloserine exacerbates negative symptoms in clozapine responders whereas full agonists, glycine and D-serine have no effects, suggesting clozapine may act indirectly as a full agonist at the GMS of the NMDA receptor. Clozapine treatment is uniquely associated with decreased substance use in patients with schizophrenia, even without psychologic intervention. Given the role of NMDA receptors in the reward circuitry and in substance dependence, it is reasonable to speculate that NMDA receptor dysfunction is a shared pathologic process in schizophrenia and co-morbid SUDs.
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PMID:Substance use disorders and Schizophrenia: a question of shared glutamatergic mechanisms. 1719 72

The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. To replicate and extend our previously reported association between the PPP3CC gene, encoding the calcineurin catalytic gamma-subunit, and schizophrenia, we examined 84 SNPs from 14 calcineurin-related candidate genes for genetic association by using 124 Japanese schizophrenic pedigrees. Four of these genes (PPP3CC, EGR2, EGR3, and EGR4) showed nominally significant association with schizophrenia. In a postmortem brain study, EGR1, EGR2, and EGR3 transcripts were shown to be down-regulated in the prefrontal cortex of schizophrenic, but not bipolar, patients. These findings raise a potentially important role for EGR genes in schizophrenia pathogenesis. Because EGR3 is an attractive candidate gene based on its chromosomal location close to PPP3CC within 8p21.3 and its functional link to dopamine, glutamate, and neuregulin signaling, we extended our analysis by resequencing the entire EGR3 genomic interval and detected 15 SNPs. One of these, IVS1 + 607A-->G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene.
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PMID:Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. 1736 May 99

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