Stressed and depressed? Check your GDNF for epigenetic repression

Abstract

Some adults fail to adapt to chronic stress, developing symptoms of depression and anxiety. In this issue of Neuron, Uchida and colleagues link maladaptive stress responses to GDNF through a comprehensive investigation of the neurotrophic factor's regulation. Further, this study is an excellent example for investigators interested in neuroepigenetics research.

Figure 1. Epigenetic Regulation of GDNF in the “Low Anxiety” B6 and “High Anxiety” BALB Mouse Strains following Chronic Stress

Chronic stress induces DNA methylation of GDNF’s promoter and recruitment of MeCP2 in the NAc of both low-anxiety B6 mice and high-anxiety BALB mice. The differential transcription rates of GDNF may be accounted for by MeCP2’s recruiting partner. In BALB mice, MeCP2 recruits HDAC2, which presumably deacetylates GDNF’s promoter, leading to the gene’s transcriptional repression. However, in B6 mice, MeCP2 recruits CREB, creating a complex demonstrated to support transcriptional activation. Together with as-yet-unknown mechanisms, epigenetic repression of GDNF leads to maladaptive stress responses in the BALB mice, including anxiety and depression-like behaviors.