Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia's nonmendelian characteristics. To investigate this assumption, we examined genome-wide (global) and gene-specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia (P<2.0×10(-6)) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R(2)=0.11, ANOVA P<0.001). Specifically, haloperidol was associated with higher ("control-like") methylation (P=0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation (P=0.002). With regard to the gene-specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S-COMT was hypermethylated in patients with schizophrenia (P=0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA-methylation signatures show promise of serving as a schizophrenia biomarker in the future.-Melas, P. A., Rogdaki, M., Ösby, U., Schalling, M., Lavebratt, C., Ekström, T. J. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset.

P11 (S100A10) has been associated with the pathophysiology of depression both in human and rodent models. Different types of antidepressants have been shown to increase P11 levels in distinct brain regions and P11 gene therapy was recently proven effective in reversing depressive-like behaviours in mice. However, the molecular mechanisms that govern P11 gene expression in response to antidepressants still remain elusive. In this study we report decreased levels of P11, associated with higher DNA methylation in the promoter region, in the prefrontal cortex of the Flinders Sensitive Line (FSL) genetic rodent model of depression. This hypermethylated pattern was reversed to normal, as indicated by the control line, after chronic administration of escitalopram (a selective serotonin reuptake inhibitor; SSRI). The escitalopram-induced hypomethylation was associated with both an increase in P11 gene expression and a reduction in mRNA levels of two DNA methyltransferases that have been shown to maintain DNA methylation in adult forebrain neurons (Dnmt1 and Dnmt3a). In conclusion, our data further support a role for P11 in depression-like states and suggest that this gene is controlled by epigenetic mechanisms that can be affected by antidepressant treatment.

BACKGROUND: Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC).MethodPPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. RESULTS: ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. CONCLUSIONS: These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.

BACKGROUND: Prepulse inhibition (PPI) of the startle response refers to a reduction in the response to a strong stimulus (pulse) if preceded shortly by a weak stimulus (prepulse). Disrupted PPI is thought to reflect abnormalities in the inhibitory control of information processing. Reduced PPI has been reported in mania, although it is not clear whether it represents a trait feature of bipolar disorder (BD). To address this issue, the present study examined whether disrupted PPI is present in individuals at high risk for BD. METHODS: Twenty-one remitted BD patients and 19 of their unaffected siblings were compared with 17 age- and gender-matched healthy volunteers on tests of acoustic startle reactivity and PPI of the startle response. RESULTS: There were no group differences in startle reactivity. Compared with healthy individuals, BD patients and their unaffected siblings showed lower PPI. In the patient group, no significant correlations were found between PPI and measures of symptom and disease severity or medication. CONCLUSIONS: This is the first study to report reduced PPI in remitted BD patients and their unaffected first-degree relatives. This finding, although in need of replication, suggests that PPI disruption may represent a trait deficit in BD associated with genetic predisposition.