The epigenetic effects of antidepressant treatment on human prefrontal cortex BDNF expression

Abstract

Convergent lines of evidence suggest that major depression is associated with neurotrophin alterations, particularly decreased brain-derived neurotrophic factor (BDNF) levels (Martinowich et al. 2007). The gene that codes for BDNF has distinct splice variants, each one regulated by a specific promoter region (Tsankova et al. 2004). Of these variants, BDNF transcript IV is the most commonly studied and its expression changes have been associated with behavioural responses following antidepressant treatment in animal models of depression (Bredy et al. 2007; Tsankova et al. 2006). In a recent study investigating mice exposed to chronic social defeat stress, a model of depression, Tsankova and colleagues (2006) reported that a 4-fold increase in histone H3 lysine 27 (H3K27) methylation was associated with repression of BDNF IV expression. Treatment of the chronically defeated mice with imipramine increased expression of BDNF IV to baseline levels, but could not reverse the alteration of H3K27 methylation. To assess the relationship between major depression, antidepressant medication, BDNF IV expression, and H3K27 methylation at the BDNF IV promoter in humans, we quantified BDNF IV expression and H3K27 tri-methylation levels in prefrontal cortex of control subjects with no psychiatric history ( n =9, Con), major depressive disorder (MDD) subjects without positive toxicology for antidepressants or history of antidepressant use ( n =11, AD−), and MDD subjects with a history of antidepressant use and with antidepressant detected in post-mortem toxicology ( n =7, AD+). Antidepressants used included: …