Location: Children's Nutrition Research CenterTitle: Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders
|MENG, XIANGLING - Baylor College Of Medicine|
|WANG, WEI - Baylor College Of Medicine|
|LU, HUI - Baylor College Of Medicine|
|HE, LING-JIE - Baylor College Of Medicine|
|CHEN, WU - Baylor College Of Medicine|
|CHAO, EUGENE - Baylor College Of Medicine|
|FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)|
|TANG, BIN - Baylor College Of Medicine|
|HERRERA, JOSE - Baylor College Of Medicine|
|SEYMOUR, MICHELLE - Baylor College Of Medicine|
|NEUL, JEFFREY - Baylor College Of Medicine|
|PEREIRA, FRED - Texas Children'S Hospital|
|TANG, JIANRONG - Baylor College Of Medicine|
|XUE, MINGSHAN - Baylor College Of Medicine|
|ZOGHBI, HUDA - Baylor College Of Medicine|
Submitted to: eLife
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/1/2016
Publication Date: 6/21/2016
Citation: Meng, X., Wang, W., Lu, H., He, L., Chen, W., Chao, E.S., Fiorotto, M.L., Tang, B., Herrera, J.A., Seymour, M.L., Neul, J.L., Pereira, F.A., Tang, J., Xue, M., Zoghbi, H.Y. 2016. Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders. eLife. 5:e14199.
Interpretive Summary: Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disabilities are thought to occur when there is an imbalance between stimulating and inhibitory brain impulses. One of these disorders is Rett Syndrome which occurs in girls and causes symptoms including anxiety, tremors, uncoordinated movements, breathing difficulties, and eating disorders. It is one of the most common genetic causes of severe intellectual disability in girls. Through the use of genetically modified mice it was previously shown that when inhibitory impulses are impaired some of the same symptoms can be reproduced. In this study, we studied the consequences of losing stimulating impulses. We found that this defect produced tremors, anxiety behavior, and an increase in food intake that resulted in marked obesity, as well as early deaths. This information is important as it can guide the development of drugs to help treat the imbalance between stimulating and inhibitory brain impulses in these pediatric patients.
Technical Abstract: Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.