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)

Recent data indicate that a significant number of schizophrenic patients are hypercortisolemic and that glucocorticoids are involved in the pathogenesis of schizophrenia. The aim of the present study was to evaluate whether behavioural schizophrenia-like changes in the lipopolysaccharide (LPS)-induced neurodevelopmental model of this brain disorder are associated with alterations in the level of plasma corticosterone, the concentration of glucocorticoid receptors and the amount of the immunophilin FKBP51, the glucocorticoid receptor co-chaperone, in the hippocampus and frontal cortex. We found that the adult offspring of prenatally LPS-treated rats showed a deficit in prepulse inhibition (PPI), an enhancement of amphetamine-induced locomotor activity, an elevated plasma level of corticosterone and a decrease in both the glucocorticoid receptor level in the hippocampus and the FKBP51 concentration in the frontal cortex. Most of these changes were reversed by the atypical antipsychotic drug clozapine, whereas chlorpromazine had no effect on PPI but attenuated the amphetamine-induced hyperactivity and normalised the hippocampal level of glucocorticoid receptors. The changes in the level of plasma corticosterone and cortical FKBP51 were attenuated by chlorpromazine in female offspring only. This study supports the hypothesis of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in schizophrenia and suggests that this hyperactivity results from a decrease in the hippocampal glucocorticoid receptor level and a decrease in FKBP51 in the frontal cortex.
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PMID:Hyperactivity of the hypothalamus-pituitary-adrenal axis in lipopolysaccharide-induced neurodevelopmental model of schizophrenia in rats: effects of antipsychotic drugs. 2103 39

Molecular abnormalities within the glucocorticoid receptor (GR) stress signaling pathway may confer, or reflect, susceptibility to stress in schizophrenia and bipolar disorder, but the extent of such abnormalities in the brain is not known. Using RNA-Seq and qPCR in two postmortem cohorts totaling 55 schizophrenia, 34 bipolar disorder and 55 control individuals, we identified increased FKBP5 and PTGES3 mRNA expression, and decreased BAG1 mRNA expression, in the prefrontal cortex in schizophrenia cases relative to controls (68.0% [p < 0.001], 26.0% [p < 0.01] and 12.1% [p < 0.05] respectively). We also observed increased FKBP5 and decreased BAG1 mRNA expression in bipolar disorder (47.5% [p < 0.05] and 14.9% [p < 0.005]). There were no diagnostic differences in steady-state FKBP51 protein levels, nor in HSPA1A, HSP90AA1, DNAJB1 or HSPB1 mRNA levels. GR, co-factor and chaperone mRNA levels were strongly correlated. These results reveal coordinated cortical dysregulation of FKBP5, PTGES3, BAG1 and GR genes within the glucocorticoid signaling pathway in psychotic illness.
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PMID:Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness. 2434 75

Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase-synapsin pathway in stress responsiveness.
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PMID:A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. 2545 92

Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sensitivity and effects on the broader function of the HPA system in response to stress. In this study, the effects of four FKBP5 polymorphisms (rs1360780, rs9470080, rs4713902, rs9394309) on IQ and eight other cognitive domains were examined in the context of exposure to childhood maltreatment in 444 cases with schizophrenia and 292 healthy controls (from a total sample of 617 cases and 659 controls obtained from the Australian Schizophrenia Research Bank; ASRB). Participants subjected to any kind of maltreatment (including physical, emotional, or sexual abuse or physical or emotional neglect) in childhood were classified as 'exposed'; cognitive functioning was measured with Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test, and IQ was estimated with the Weschler Test of Adult Reading. Hierarchical regressions were used to test the main effects of genotype and childhood maltreatment, and their additive interactive effects, on cognitive function. For rs1360870, there were significant main effects of genotype and childhood maltreatment, and a significant interaction of genotype with childhood trauma affecting attention in both schizophrenia and healthy participants (C-homozygotes in both groups showed worse attention in the context of maltreatment); in SZ, this SNP also affected global neuropsychological function regardless of exposure to childhood trauma, with T-homozygotes showing worse cognition than other genotypes. The mechanisms of trauma-dependent effects of FKBP5 following early life trauma deserve further exploration in healthy and psychotic samples, in the context of epigenetic effects and perhaps epistasis with other genes. Study of these processes may be particularly informative in subgroups exposed to various other forms of early life adversity (i.e., birth complications, immigration).
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PMID:Do common genotypes of FK506 binding protein 5 (FKBP5) moderate the effects of childhood maltreatment on cognition in schizophrenia and healthy controls? 2642 18

The molecular basis of vulnerability to stress during the adolescent period is largely unknown. To identify potential molecular mediators that may play a role in stress-induced behavioral deficits, we imposed social isolation on a genetically vulnerable mouse model. We report that 3-week (5-8 weeks of age) adolescent stress in combination with disrupted-in-schizophrenia 1 (Disc1) genetic risk elicits alterations in DNA methylation of a specific set of genes, tyrosine hydroxylase, brain-derived neurotrophic factor and FK506 binding protein 5. The epigenetic changes in the mesocortical dopaminergic neurons were prevented when animals were treated with a glucocorticoid receptor (GR) antagonist RU486 during social isolation, which implicates the role for glucocorticoid signaling in this pathological event. We define the critical period of GR intervention as the first 1-week period during the stress regimen, suggesting that this particular week in adolescence may be a specific period of maturation and function of mesocortical dopaminergic neurons and their sensitivity to glucocorticoids. Our study may also imply the clinical significance of early detection and prophylactic intervention against conditions associated with adolescent social stress in individuals with genetic risk.
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PMID:A critical period of vulnerability to adolescent stress: epigenetic mediators in mesocortical dopaminergic neurons. 2690 23

Major depressive disorder (MDD) is a leading contributor to the global burden of disease. However, the causal relationship of risk factors, such as genetic predisposition or experience of augmented stress, remain unknown. Numerous studies in humans and rodents have implicated brain-derived neurotrophic factor (BDNF) in MDD pathology, as a genetic risk factor and a factor regulated by stress. Until now, the majority of preclinical studies have employed genetically modified mice as their model of choice. However, mice display a limited behavioural repertoire and lack expression of circulating BDNF, which is present in rats and humans. Therefore, heterozygous BDNF (BDNF+/- ) rats were tested for affective behaviours and accompanying expression of key genes associated with affective disorders in the brain. We found that BDNF+/- rats, which have reduced BDNF levels in brain and plasma, displayed symptoms of anhedonia, a core symptom of MDD, and anxiety-like behaviour, but no behavioural despair or cognitive impairments. This was accompanied by changes in the expression of genes that are implicated in modulation of the stress response and affective disorders. Hence, glucocorticoid receptor, neuregulin 1 and disrupted-in-schizophrenia 1 gene expression were upregulated in the prefrontal cortex of BDFN+/- rats, whereas FK506 binding protein 5 levels were decreased in the hippocampus. We conclude that a reduction in BDNF levels alters expression of genes associated with affective disorders, which may contribute to the development of depressive-like symptoms.
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PMID:BDNF+/- rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders. 3054 75