Alteration in the epigenetic regulation following overexpression of glucocorticoid receptor in the mice forebrain

Chaudhury S, Hebda-Bauer EK, Wei Q, Sharma V, Seasholtz A, Watson SJ, Akil H
Society for Neuroscience. 2013.


Stress and anxiety-related disorders alter the Hypothalamo-Pituitary-Adrenal (HPA) axis. Glucocorticoids, which play a key role in the stress response, mediate their actions via the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). GR is widely distributed in the brain and is known to play multiple roles including mediating neuroendocrine negative feedback and modulating cognitive function. Moreover, our laboratory has implicated GR in affect regulation, by showing that overexpression of GR in the forebrain increases anxiety-like and depression-like behaviors relative to wild type. Constitutive GR overexpressing mice (GRov), while more prone to anxiety and depression, are also highly sensitive to antidepressants and show enhanced sensitization to cocaine, demonstrating increase lability in their affective responses- a hallmark of bipolar disorder. However, the cellular basis for this phenotype remains to be fully elucidated. As post-translational modifications of the histones can influence phenomena such as drug addiction, memory formation and stress responses, we asked whether epigenetic regulation may play a role in the phenotype of these GRov mice. Here we report that there is a differential level of various repressive and activated histone proteins in the hippocampus and amygdala of GRov compared to wild type mice. Moreover, the binding of modified histones at gene promoters that are implicated in stress responsiveness and anxiety behavior also differs between GRov and wild type mice. We suggest that overexpression of GR in the forebrain is responsible for altering the levels of modified histones and their binding at specific gene promoters implicated in affect regulation. This may lead to a unique behavioral phenotype that mimics the affective instability observed in bipolar illness.{8D2A5BEC-4825-4CD6-9439-B42BB151D1CF}