Abstract
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 GABAA 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.
Highlights
Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein involved in the transcriptional repression of target genes (Chahrour and Zoghbi, 2007; Lyst and Bird, 2015; Qiu, 2018)
We explored whether ChatMecp2-/y mice showed spontaneous immobility behavior
We compared the effect of L-838,417 on GABAergic current and found that both the frequency and amplitude of sIPSC have been increased after treatment (Figure 3—figure supplement 2E,F). These results indicate that MeCP2 deficiency in cholinergic interneurons enhances inhibitory synaptic transmission, which could be ascribed to increased a2-GABAA expression
Summary
MeCP2 is a nuclear protein involved in the transcriptional repression of target genes (Chahrour and Zoghbi, 2007; Lyst and Bird, 2015; Qiu, 2018). Clinical research has implicated the NAc as one of the affected brain regions in RTT patients (Reiss et al, 1993; Subramaniam et al, 1997). Considering these findings, investigating the potential role of MeCP2 in regulating the function of NAc cholinergic interneurons in associative learning and memory would be of interest. We explored the cellular and molecular mechanisms underlying learning and memory deficits in a mouse model of RTT and discovered a previously unknown role of the NAc in regulating fear learning
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