Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression

Abstract

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.

The Flinders Sensitive Line Rat Model of Depression—25 Years and Still Producing

“…It was found that decreased levels of P11 were associated with higher DNA methylation in the promoter region of the prefrontal cortex of FSL rats than was seen in FRL rats. The hypermethylated pattern of the FSL rats was returned to levels seen in the FRL rats following chronic administration of the selective serotonin reuptake inhibitor escitalopram (Melas et al, 2011).…”

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

“…Second, DNA methylation research in humans has been mostly correlational, allowing no inferences about cause and effect. For instance, much of the literature implies that DNA methylation induced by stress might increase the risk for psychopathology, but it is reasonable to assume that psychopathology itself via, for example, depression-induced alterations of other biological systems or past or current treatment 126,159 could affect the epigenome. Intervention studies or longitudinal studies in at-risk human samples (e.g., firstdegree relatives) are needed to disentangle cause and effect.…”

Molecular and Cellular Mechanisms of Antidepressant Action

“…For example, antidepressant-induced changes in the expression of both BDNF and P11 have been attributed to epigenetic mechanisms, specifically increased histone acetylation and reduced DNA methylation, respectively (Tsankova et al 2006;Lopez et al 2012;Melas et al 2012). Evidence such as this is encouraging research into the antidepressant potential of drugs targeted at epigenetic mechanisms.…”