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Methyl-CpG-binding protein 2 (MeCP2) encoded by the  MECP2  gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT).  Mecp2 -deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that  Mecp2  gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in  Mecp2 -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.

MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning