Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes

Hsiao-Tuan Chao, Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Shiaoching Gong, Hui-Chen Lu, Nathaniel Heintz, Marc Ekker, John L. R. Rubenstein, Jeffrey L. Noebels, Christian Rosenmund () and Huda Y. Zoghbi ()
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Hsiao-Tuan Chao: Baylor College of Medicine, Houston, Texas 77030, USA
Hongmei Chen: Baylor College of Medicine
Rodney C. Samaco: Baylor College of Medicine
Mingshan Xue: Baylor College of Medicine, Houston, Texas 77030, USA
Maria Chahrour: Baylor College of Medicine
Jong Yoo: Baylor College of Medicine
Jeffrey L. Neul: Baylor College of Medicine
Shiaoching Gong: The Rockefeller University and Howard Hughes Medical Institute
Hui-Chen Lu: Baylor College of Medicine
Nathaniel Heintz: The Rockefeller University and Howard Hughes Medical Institute
Marc Ekker: Center for Advanced Research in Environmental Genomics, University of Ottawa, Ontario K1N 6N5, Canada
John L. R. Rubenstein: University of California
Jeffrey L. Noebels: Baylor College of Medicine, Houston, Texas 77030, USA
Christian Rosenmund: Baylor College of Medicine, Houston, Texas 77030, USA
Huda Y. Zoghbi: Baylor College of Medicine, Houston, Texas 77030, USA

Nature, 2010, vol. 468, issue 7321, 263-269

Abstract: Abstract Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (γ-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

Date: 2010
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DOI: 10.1038/nature09582

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