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GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes

Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is ch...

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Detalles Bibliográficos
Autores principales: Chao, Hsiao-Tuan, Chen, Hongmei, Samaco, Rodney C., Xue, Mingshan, Chahrour, Maria, Yoo, Jong, Neul, Jeffrey L., Gong, Shiaoching, Lu, Hui-Chen, Heintz, Nathaniel, Ekker, Marc, Rubenstein, John L.R., Noebels, Jeffrey L., Rosenmund, Christian, Zoghbi, Huda Y.
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057962/
https://www.ncbi.nlm.nih.gov/pubmed/21068835
http://dx.doi.org/10.1038/nature09582
Descripción
Sumario:Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from γ-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and -2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.