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

Author

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  • Hsiao-Tuan Chao

    (Baylor College of Medicine, Houston, Texas 77030, USA
    Baylor College of Medicine)

  • Hongmei Chen

    (Baylor College of Medicine)

  • Rodney C. Samaco

    (Baylor College of Medicine)

  • Mingshan Xue

    (Baylor College of Medicine, Houston, Texas 77030, USA
    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.).)

  • Maria Chahrour

    (Baylor College of Medicine)

  • Jong Yoo

    (Baylor College of Medicine)

  • Jeffrey L. Neul

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Baylor College of Medicine)

  • Shiaoching Gong

    (The Rockefeller University and Howard Hughes Medical Institute)

  • Hui-Chen Lu

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, 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
    Baylor College of Medicine
    Baylor College of Medicine)

  • Christian Rosenmund

    (Baylor College of Medicine, Houston, Texas 77030, USA
    Baylor College of Medicine
    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.).)

  • Huda Y. Zoghbi

    (Baylor College of Medicine, Houston, Texas 77030, USA
    Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

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.

Suggested Citation

  • 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 &, 2010. "Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes," Nature, Nature, vol. 468(7321), pages 263-269, November.
    • Handle: RePEc:nat:nature:v:468:y:2010:i:7321:d:10.1038_nature09582
    DOI: 10.1038/nature09582
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    Cited by:

    1. Yu-Jun Wang & Gui-Ying Zan & Cenglin Xu & Xue-Ping Li & Xuelian Shu & Song-Yu Yao & Xiao-Shan Xu & Xiaoyun Qiu & Yexiang Chen & Kai Jin & Qi-Xin Zhou & Jia-Yu Ye & Yi Wang & Lin Xu & Zhong Chen & Jing, 2023. "The claustrum-prelimbic cortex circuit through dynorphin/κ-opioid receptor signaling underlies depression-like behaviors associated with social stress etiology," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Lauren Rylaarsdam & Jennifer Rakotomamonjy & Eleanor Pope & Alicia Guemez-Gamboa, 2024. "iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Xin-Yan Zhang & Karen Spruyt, 2022. "Literature Cases Summarized Based on Their Polysomnographic Findings in Rett Syndrome," IJERPH, MDPI, vol. 19(6), pages 1-17, March.
    4. Ya-Nan Zhao & Jian-Bo Jiang & Shi-Yuan Tao & Yang Zhang & Ze-Ka Chen & Wei-Min Qu & Zhi-Li Huang & Su-Rong Yang, 2022. "GABAergic neurons in the rostromedial tegmental nucleus are essential for rapid eye movement sleep suppression," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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