Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus.
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) cholinergic 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.
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Ying
Y
Zhang
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Shu-Xia
SX
Cao
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Peng
P
Sun
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Hai-Yang
HY
He
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Ci-Hang
CH
Yang
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Xiao-Juan
XJ
Chen
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Chen-Jie
CJ
Shen
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Xiao-Dong
XD
Wang
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Zhong
Z
Chen
Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093-0357, USA.
Darwin K
DK
Berg
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Soft Matter Research Center, Zhejiang University, Hangzhou, Zhejiang, China.
Shumin
S
Duan
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Soft Matter Research Center, Zhejiang University, Hangzhou, Zhejiang, China.
Xiao-Ming
XM
Li
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002421:Caudate Nucleus / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism*; D004198:Disease Susceptibility; D017353:Gene Deletion; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009538:Nicotine / Q000494:pharmacology; D010641:Phenotype; D016548:Prosencephalon / Q000378:metabolism; D015518:Rett Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D012640:Seizures / Q000150:complications / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D051783:Methyl-CpG-Binding Protein 2; C498513:PNU-282987; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine