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

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.

Pubmed ID: 21068835

Authors

  • Chao HT
  • Chen H
  • Samaco RC
  • Xue M
  • Chahrour M
  • Yoo J
  • Neul JL
  • Gong S
  • Lu HC
  • Heintz N
  • Ekker M
  • Rubenstein JL
  • Noebels JL
  • Rosenmund C
  • Zoghbi HY

Journal

Nature

Publication Data

November 11, 2010

Associated Grants

  • Agency: PHS HHS, Id: 29709
  • Agency: NIMH NIH HHS, Id: F31MH078678
  • Agency: NICHD NIH HHS, Id: HD024064
  • Agency: NICHD NIH HHS, Id: HD053862
  • Agency: NINDS NIH HHS, Id: K08 NS052240
  • Agency: NINDS NIH HHS, Id: K08 NS052240-01
  • Agency: NINDS NIH HHS, Id: K08 NS052240-02
  • Agency: NINDS NIH HHS, Id: K08 NS052240-03
  • Agency: NINDS NIH HHS, Id: K08 NS052240-04
  • Agency: NINDS NIH HHS, Id: K08 NS052240-05
  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: NICHD NIH HHS, Id: P30 HD024064-22
  • Agency: NICHD NIH HHS, Id: R01 HD062553
  • Agency: NINDS NIH HHS, Id: R01 NS048884
  • Agency: NINDS NIH HHS, Id: R01 NS057819
  • Agency: NINDS NIH HHS, Id: R01 NS057819-04
  • Agency: NINDS NIH HHS, Id: R01 NS057819-05
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Autistic Disorder
  • Brain
  • Compulsive Behavior
  • Disease Models, Animal
  • Electroencephalography
  • Genotype
  • Glutamate Decarboxylase
  • Hippocampus
  • Homeodomain Proteins
  • Inhibitory Postsynaptic Potentials
  • Long-Term Potentiation
  • Male
  • Methyl-CpG-Binding Protein 2
  • Mice
  • Mice, Transgenic
  • Neural Inhibition
  • Neuronal Plasticity
  • Neurons
  • Phenotype
  • Presynaptic Terminals
  • Psychomotor Disorders
  • Reflex, Startle
  • Respiration
  • Rett Syndrome
  • Self-Injurious Behavior
  • Signal Transduction
  • Stereotypic Movement Disorder
  • Survival Rate
  • Synaptic Transmission
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • gamma-Aminobutyric Acid