title: Selective preservation of cholinergic MeCP2 rescues specific Rett-syndrome-like phenotypes in MeCP2stopmice.
abstract: RTT is a neurodevelopmental disorder characterized by growth regression, motor dysfunction, stereotypic hand movements, and autism features. Typical Rett syndrome (RTT) is predominantly caused by mutations in X-linked MeCP2 gene which encodes methyl-CpG-binding protein 2 (MeCP2). The brain-abundant MeCP2 protein mainly functions as a transcriptional regulator for neurodevelopment-associated genes. Specific functions of MeCP2 in certain neuron types remain to be known. Although cholinergic system is an important modulating system in brain, how MeCP2 in cholinergic neurons contribute to RTT has not been clearly understood. Here we use a mouse model with selectively activated endogenous MeCP2 in cholinergic neurons in otherwise MeCP2stopmice to determine the cholinergic MeCP2 effects on rescuing the RTT-like phenotypes. We found cholinergic MeCP2 preservation could reverse some aspects of the RTT-like phenotypes in mice including hypolocomotion and increased anxiety level, and delay the onset of underweight, instead of improving the hypersocial abnormality and the poor general conditions such as short lifespan, low brain weight, and increasing severity score. Our findings suggest that selective activation of cholinergic MeCP2 is sufficient to reverse the locomotor impairment and increased anxiety-like behaviors at least in early symptomatic stage, supporting future development of RTT therapies associated with cholinergic system.
authors.affiliation: Department of Children Health Care, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Children Health Care, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
authors.forename: Zhefeng
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Children Health Care, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Children Health Care, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. Electronic address: zzy_ees@163.com.
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000473:pathology; D001835:Body Weight; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism; D004195:Disease Models, Animal; D006339:Heart Rate; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D053580:Muscle Strength / Q000502:physiology; D010641:Phenotype; D065808:Prepulse Inhibition / Q000502:physiology; D015518:Rett Syndrome / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D012919:Social Behavior
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D002795:Choline O-Acetyltransferase
keywords: Anxiety; Behaviour; Cholinergic neurons; Locomotion; MeCP2; Rett syndrome