Loss of MeCP2 in cholinergic neurons causes part of RTT- like phenotypes via α7 receptor in hippocampus

• Published in: Cell research Vol. 26; no. 6; pp. 728 - 742
• Main Authors: Zhang, Ying, Cao, Shu-Xia, Sun, Peng, He, Hai-Yang, Yang, Ci-Hang, Chen, Xiao-Juan, Shen, Chen-Jie, Wang, Xiao-Dong, Chen, Zhong, Berg, Darwin K, Duan, Shumin, Li, Xiao-Ming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2016; Nature Publishing Group
• Subjects: 631/378/1595/1554; 631/45/612/1239; 631/80/86; 692/699/476; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Benzamides - pharmacology; Biomedical and Life Sciences; Bridged Bicyclo Compounds - pharmacology; Caudate Nucleus - metabolism; Cell Biology; Cholinergic Neurons - metabolism; Disease Susceptibility; Gene Deletion; Hippocampus - drug effects; Hippocampus - metabolism; Life Sciences; Male; Methyl-CpG-Binding Protein 2 - metabolism; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Nicotine - pharmacology; Original; original-article; Phenotype; Prosencephalon - metabolism; Rett Syndrome - complications; Rett Syndrome - metabolism; Rett Syndrome - pathology; RTT; Seizures - complications; Seizures - pathology; Signal Transduction - drug effects; 乙酰胆碱受体; 基因突变; 海马; 社会关系; 胆碱乙酰转移酶; 胆碱能神经元; 表型; MeCP2; RTT-like phenotypes; cholinergic system; Rett syndrome
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2016.48

Mutations in the X-linked MECP2 gene cause Rett syndrome （RTT）, an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain （BF） eholinergic neurons rather than in the caudate putamen of conditional knockout （Chat-Mecp2-/y） mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2^-/y mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2^-/y mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.