| Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. | |
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MedLine Citation:
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PMID: 21068835 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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; Huda Y Zoghbi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 468 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-11 Completed Date: 2010-12-23 Revised Date: 2012-04-06 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 263-9 Citation Subset: IM |
Affiliation:
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]Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Autistic Disorder / complications, genetics, pathology, physiopathology* Brain / cytology Compulsive Behavior / complications, genetics, physiopathology Disease Models, Animal Electroencephalography Genotype Glutamate Decarboxylase / metabolism Hippocampus / pathology, physiopathology Homeodomain Proteins / genetics Inhibitory Postsynaptic Potentials Long-Term Potentiation Male Methyl-CpG-Binding Protein 2 / deficiency*, genetics, metabolism* Mice Mice, Transgenic Neural Inhibition Neuronal Plasticity Neurons / metabolism Phenotype Presynaptic Terminals / metabolism Psychomotor Disorders / complications, genetics, physiopathology Respiration Rett Syndrome / complications, genetics, pathology, physiopathology* Self-Injurious Behavior / complications, genetics, physiopathology Signal Transduction* Startle Reaction / genetics Stereotypic Movement Disorder / complications, genetics, pathology, physiopathology* Survival Rate Synaptic Transmission Vesicular Inhibitory Amino Acid Transport Proteins / genetics gamma-Aminobutyric Acid / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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29709//PHS HHS; F31MH078678/MH/NIMH NIH HHS; HD024064/HD/NICHD NIH HHS; HD053862/HD/NICHD NIH HHS; K08 NS052240-01/NS/NINDS NIH HHS; K08 NS052240-02/NS/NINDS NIH HHS; K08 NS052240-03/NS/NINDS NIH HHS; K08 NS052240-04/NS/NINDS NIH HHS; K08 NS052240-05/NS/NINDS NIH HHS; P30 HD024064-22/HD/NICHD NIH HHS; R01 HD062553-03/HD/NICHD NIH HHS; R01 NS057819-04/NS/NINDS NIH HHS; R01 NS057819-05/NS/NINDS NIH HHS; //Howard Hughes Medical Institute; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Dlx5 protein, mouse; 0/Dlx6 protein, mouse; 0/Homeodomain Proteins; 0/Mecp2 protein, mouse; 0/Methyl-CpG-Binding Protein 2; 0/Vesicular Inhibitory Amino Acid Transport Proteins; 0/Viaat protein, mouse; 56-12-2/gamma-Aminobutyric Acid; EC 4.1.1.15/Glutamate Decarboxylase; EC 4.1.1.15/glutamate decarboxylase 1; EC 4.1.1.15/glutamate decarboxylase 2 |
| Comments/Corrections | |
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