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

• Published in: The international journal of neuropsychopharmacology Vol. 15; no. 5; pp. 669 - 679
• Main Authors: Melas, Philippe A., Rogdaki, Maria, Lennartsson, Andreas, Björk, Karl, Qi, Hongshi, Witasp, Anna, Werme, Martin, Wegener, Gregers, Mathé, Aleksander A., Svenningsson, Per, Lavebratt, Catharina
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.06.2012; Oxford University Press
• Subjects: Animal models; Animals; Annexin A2 - genetics; Annexin A2 - metabolism; Antidepressants; Brain; Calcium-binding protein; citalopram; Citalopram - pharmacology; Cortex (prefrontal); Data processing; Depression; Depressive Disorder - drug therapy; Depressive Disorder - genetics; Depressive Disorder - metabolism; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - drug effects; DNA methylation; DNA methyltransferase; DNMT1 protein; Epigenetics; Epigenomics; Female; Forebrain; Gene expression; Gene Expression Regulation - drug effects; Mental depression; Molecular modelling; Neurons; p11 gene; Prefrontal Cortex - drug effects; Promoters; Rats; RNA, Messenger - biosynthesis; S100 protein; S100 Proteins - genetics; S100 Proteins - metabolism; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - pharmacology; DNA methylation; Depression; escitalopram; P11 (S100A10); epigenetics
• ISSN: 1461-1457; 1469-5111; 1469-5111
• DOI: 10.1017/S1461145711000940

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.