MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning

Abstract

Methyl-CpG-binding protein 2 (MeCP2) encoded by the <i>MECP2</i> gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT). <i>Mecp2</i>-deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that <i>Mecp2</i> gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in <i>Mecp2</i>-deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABA_A receptors. With MeCP2 restoration, opto- and chemo-genetic activation, and RNA interference in ChAT-expressing interneurons of the NAc, impaired fear retrieval was rescued. Taken together, these results reveal a previously unknown role of MeCP2 in NAc cholinergic interneurons in fear regulation, suggesting that modulation of neurons in the NAc may ameliorate fear-related disorders.