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

Nature volume 468, pages 263269 (11 November 2010) | Download Citation


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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We thank G. Schuster for pronuclear injections; C. Spencer and R. Paylor for advice on behavioural assays; M. Albright for advice on slice electrophysiology; R. Atkinson, Y. Sun, J. Tang and S. Vaishnav for technical advice; V. Brandt for editorial advice. This work was supported by the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke (NINDS) HD053862, the Simons Foundation, the Rett Syndrome Research Trust (H.Y.Z.); the Intellectual and Developmental Disability Research Centers HD024064 (H.Y.Z., C.R. and J. L. Noebels); NINDS 29709 (J. L. Noebels); the International Rett Syndrome Foundation (C.R.); Autism Speaks (R.C.S.); the National Institute of Mental Health F31MH078678, Baylor Research Advocates for Student Scientists and McNair Fellowships (H.-T.C.).

Author information

Author notes

    • Mingshan Xue
    •  & Christian Rosenmund

    Present addresses: Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA (M.X.); Neurocure, Neuroscience Research Center, Charite Universitaetsmedizin Berlin, 10117, Germany (C.R.).


  1. Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA

    • Hsiao-Tuan Chao
    • , Mingshan Xue
    • , Jeffrey L. Noebels
    • , Christian Rosenmund
    •  & Huda Y. Zoghbi
  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Hsiao-Tuan Chao
    • , Hongmei Chen
    • , Rodney C. Samaco
    • , Maria Chahrour
    • , Jeffrey L. Noebels
    • , Christian Rosenmund
    •  & Huda Y. Zoghbi
  3. Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Jong Yoo
    • , Jeffrey L. Noebels
    •  & Huda Y. Zoghbi
  4. Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Jeffrey L. Neul
    • , Hui-Chen Lu
    •  & Huda Y. Zoghbi
  5. Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas 77030, USA

    • Jeffrey L. Neul
    • , Hui-Chen Lu
    •  & Huda Y. Zoghbi
  6. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA

    • Huda Y. Zoghbi
  7. The Rockefeller University and Howard Hughes Medical Institute, New York, New York 10021, USA

    • Shiaoching Gong
    •  & Nathaniel Heintz
  8. Center for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ontario K1N 6N5, Canada

    • Marc Ekker
  9. Department of Psychiatry, University of California, San Francisco, California 94158, USA

    • John L. R. Rubenstein


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H.-T.C. and H.Y.Z. conceived the study. H.-T.C., M.X., C.R. and H.Y.Z. designed experiments with input from H.C., R.C.S., J. L. Neul, H.-C.L. and J. L. Noebels. H.-T.C., H.C., R.C.S., M.X., M.C., J.Y. and J. L. Neul performed experiments. H.-T.C., H.C., M.X., J.Y. and J. L. Neul analysed data; H.-T.C., M.X., C.R. and H.Y.Z. interpreted data with input from H.C., R.C.S., J.Y., J. L. Neul, H.-C.L. and J. L. Noebels. S.G. and N.H. provided reagents for generation of Viaat–Cre; J.L.R.R. and M.E. provided Dlx5/6–Cre mice. H.-T.C., M.X. and H.Y.Z. wrote the manuscript and H.C., R.C.S., M.C., J.L. Neul, S.G., J.L.R.R, J. L. Noebels and C.R. provided input.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Christian Rosenmund or Huda Y. Zoghbi.

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