MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning.

Abstract

Methyl-CpG-binding protein 2 (MeCP2) encoded by thegene is a transcriptional regulator whose mutations cause Rett syndrome (RTT).-deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed thatgene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in-deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABAreceptors. 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.