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)

Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB(TK+) mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB(TK+) mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB(TK+) mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB(TK+) was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia.
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PMID:Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. 1594 Mar 4

Brain-derived neurotrophic factor (BDNF) regulates a variety of neuromodulatory processes during development, as well as in adulthood. It has been proposed as a risk factor for schizophrenia. We have investigated a possible association between schizophrenia and the C-270T polymorphism in the brain-derived neurotrophic factor (BDNF) gene in 397 schizophrenic patients and 380 control subjects. The diagnosis of schizophrenia was made for each patient by at least two psychiatrists, using DSM-IV and ICD-10 criteria in structured clinical interviews for DSM-IV Axis I disorders (SCID). No association was found between schizophrenia and the analyzed polymorphism, for either genotype or allele distribution (for genotype: p=0.513, for alleles: p=0.812). Differences were not statistically significant when analyzed separately by sex. For males, the differences for genotype distribution and allele frequency were p=0.078 and p=0.162 respectively and for females: p=0.441 and p=0.315. Thus, our data indicate that variations in the BDNF gene are unlikely to be an important factor in susceptibility to schizophrenia.
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PMID:No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia. 1594 51

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.
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PMID:Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. 1595 69

Prepulse inhibition (PPI) is a cross-species measure of sensorimotor gating. PPI deficits have been associated with a number of neuropsychiatric disorders, including schizophrenia. Differential PPI has been demonstrated also across various inbred mouse strains; however, the molecular mechanisms underlying these differences in sensorimotor gating remain unclear. Here, we sought to identify gene expression in the medial prefrontal cortex (mPFC) of mice associated with PPI using a laser microdissection and microarray analysis-based approach. C57BL/6 mouse substrains were used for the study as they have dramatically different PPI. Transcriptional analysis of closely related substrains was predicted to reduce the detection of genetic variation incidental to the phenotype. Microarray analysis comparing the mPFC of C57BL/6J to C57BL/6NHsd mice revealed neurotransmission- and cellular stress-related transcriptional responses associated with lower PPI. Down-regulation of metabotropic glutamate receptor 5, phospholipase C, and inositol monophosphatase 1 gene expression suggest altered phosphoinositide signaling, while decreased expression of a gamma-amino-butyric acid (GABA)A receptor subunit implies changes in GABAergic signaling. Genes involved in neuronal excitation and protection were also differentially expressed, including up-regulation of five immediate early genes and anti-apoptotic/survival factors as Bcl2-associated athanogene 3 and brain-derived neurotrophic factor. These data support previous findings of genetic influences on PPI, and provide novel insights into the molecular mechanisms regulating sensorimotor gating.
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PMID:Neurotransmission- and cellular stress-related gene expression associated with prepulse inhibition in mice. 1596 Nov 83

Schizophrenia and affective disorder have been considered to be nosologically and etiologically distinct disorders. This postulate is challenged by progress in new biological research. Both disorders are strongly influenced by genetic factors; thus genetic research is a main contributor to this discussion. We review current evidence of the genetic relationship between schizophrenia and affective disorders, mainly bipolar disorder (the various genetic research methods have been particularly applied to bipolar disorder). Recent family and twin studies reveal a growing consistency in demonstrating cosegregation between both disorders which is difficult to detect with certainty given the low base rates. Systematic molecular genetic search for specific genes impacting on either disorder has now identified one gene which is apparently involved in both disorders (G72/G30); other candidate genes reveal some evidence to present as susceptibility genes with very modest effects for each of both disorders, although not consistently so (e. g., COMT, BDNF). There is room for speculation about other common susceptibility genes, given the overlap between candidate regions for schizophrenia and those for bipolar disorder emerging from linkage studies.
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PMID:Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? 1599 99

One of the main features of schizophrenia is its age at onset in early adulthood. Dopaminergic dysregulation is the most documented neurobiological factor that may be involved in triggering schizophrenia. Recent findings on neurodevelopmental processes show that the brain-derived neurotrophic factor plays a critical role in the development of mesolimbic dopaminergic-related systems and regulates the expression of dopamine D3 receptors. In this study, we examine whether an interaction between dopamine D3 receptors and brain-derived neurotrophic factor gene variants influences age at onset in patients with schizophrenia. Our findings show that this gene-gene interaction was significantly associated with an earlier emergence of psychosis by 3 years.
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PMID:Age at onset of schizophrenia: interaction between brain-derived neurotrophic factor and dopamine D3 receptor gene variants. 1605 49

HO-2 is a constitutive isoform of heme oxygenase (HO), a microsomal enzyme that catalyzes the cleavage of the heme ring to form ferrous iron, carbon monoxide, and biliverdin. In contrast to HO-1, which is inducible, HO-2 is not responsive to stimuli tested to date except for prolonged exposure to the adrenal glucocorticoids (GCs). Previous studies have shown that high GC concentrations or stress damage or kill hippocampal neurons. In the present study, it was found that chronic restraint stress decreased HO-2 protein levels in hippocampal neurons, as demonstrated by immunohistochemistry and Western blot analysis. Moreover, our results showed that the combination of 2.5mg/kg of venlafaxine and 5mg/kg of quetiapine effectively prevented the HO-2 protein decrease in hippocampal neurons of stressed rats, whereas either of the drugs alone did not show any effect. At higher dose levels, both quetiapine (10mg/kg) and venlafaxine (5mg/kg) produced significant effects comparable to that of their combination. Quetiapine is an atypical antipsychotic and venlafaxine an antidepressant. In previous studies, these two drugs have been shown to prevent or protect against the stress-induced decrease in hippocampal neurogenesis and BDNF expression. These data suggest that both quetiapine and venlafaxine share the hippocampus as their common target by enhancing hippocampal resilience, which may be impaired in patients with schizophrenia or depression.
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PMID:Quetiapine and venlafaxine synergically regulate heme oxygenase-2 protein expression in the hippocampus of stressed rats. 1611 34

Quetiapine is an atypical antipsychotic effective in treating the positive, negative, and cognitive symptoms of patients with schizophrenia. Our previous study has shown that chronic administration of quetiapine attenuates the decrease in levels of brain-derived neurotrophic factor (BDNF) in the hippocampi of rats subjected to chronic-restraint stress. In the present study, we investigated the effects of quetiapine on hippocampal neurogenesis that had been compromised in stressed rats. Newborn cells in the hippocampus were labeled by bromodeoxyuridine (BrdU), and immature neurons were detected immunohistochemically using an antibody against phosphorylated cAMP response element-binding protein (pCREB). The restrained rats (4 h/day for 7 days) showed lower levels of hippocampal neurogenesis indicated by decreased numbers of BrdU-labeled and pCREB-positive cells. Post-stress administration of quetiapine (10 mg/kg) for 7 or 21 days reversed the stress-induced suppression of hippocampal neurogenesis, evidenced in the numbers of BrdU-labeled and pCREB-positive cells that are comparable to those in non-stressed rats but higher than those in the vehicle-treated rats. The results may help us understand the therapeutic effects of quetiapine on cognitive deficits in patients with schizophrenia and depression, in which the structure and functions of the hippocampus are implicated.
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PMID:Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress. 1627 9

It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry.
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PMID:Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. 1631 75

Impressive advances in the last decade have been made in the genetics and neuroscience of neuropsychiatric illness. Synergies between complex genetics, elaboration of intermediate phenotypes (Egan et al. (2004) Schizophrenia. London: Blackwell) and novel applications in neuroimaging (Bookheimer et al. (2000) N Engl J Med, 343, 450-456) are revealing the effects of positively associated disease alleles on aspects of neurological function. Genes such as NRG-1, DISC1, RGS4, COMT, PRODH, DTNBP1, G72, DAAO, GRM3 (Harrison and Weinberger (2005) Mol Psychiatry, 10, 40-68) and others have been implicated in schizophrenia along with 5-HTTPR (Ogilvie et al. (1996) Lancet, 347, 731-733; Caspi et al. (2003) Science, 301, 386-389) and BDNF (Geller et al. (2004) Am J Psychiatry, 161, 1698-1700) in affective disorders. As the genetics and complex neurocircuits of these and disorders are being untangled, parallel applications in pharmacogenomics and gene-based drug metabolism are shaping a drive for personalized medicine. Genetic research and pharmacogenomics suggest that the subcategorization of individuals based on various sets of susceptibility alleles will make the treatment of neuropsychiatric and other illnesses more predictable and effective.
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PMID:Psychiatric genetics--the new era: genetic research and some clinical implications. 1636 81


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