GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes

By Hsiao-Tuan Chao, Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria H. Chahrour, Jong W. Yoo, J. Neul, Shiaoching Gong, Hui-Chen Lu, N. Heintz and 5 more. Nature, 2010

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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.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fca4b0e6f7727ba7cc4c8d78d5fd38048868fb6a

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Citations in the corpus

Principles of connectivity among morphologically defined cell types in adult neocortex (2015, neutral): “cell type–specific connectivity change in cortical microcircuits (18, 38, 39), such a detailed blueprint of cortical microcircuits could serve as an invaluable platform for screening and pinpoint-”
Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism (2012, background): “Self-grooming is also increased in several other mouse strains with relevance to autism (BTBR, and Fmr1, MeCP2 and CNTNAP2 KO mice) (McNaughton et al., 2008; McFarlane et al., 2008; Chao et al., 2010; Peñagarikano et al., 2011).”
Structural plasticity of GABAergic axons is regulated by network activity and GABAA receptor activation (2013, background): “Small and local imbalances can already have profound effects on behavior, reminiscent of diseases such as autism or schizophrenia (Chao et al., 2010; Yizhar et al., 2011; Han et al., 2012).”