GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes

Chao, Hsiao-Tuan; Chen, Hongmei; Samaco, Rodney C; Xue, Mingshan; Chahrour, Maria H.; Yoo, Jong; Neul, Jeffrey L.; Gong, Shiaoching; Lu, Hui-Chen; Heintz, Nathaniel; Ekker, Marc; Rubenstein, John L.R.; Noebels, Jeffrey L.; Rosenmund, Christian; Zoghbi, Huda Y.

doi:10.1038/nature09582

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GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes

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Author(s): Hsiao-Tuan Chao ¹ ^, ² , Hongmei Chen ² , Rodney C. Samaco ² , Mingshan Xue ¹ , Maria Chahrour ² , Jong Yoo ³ , Jeffrey L. Neul ⁴ ^, ⁵ , Shiaoching Gong ⁷ , Hui-Chen Lu ⁴ ^, ⁵ , Nathaniel Heintz ⁷ , Marc Ekker ⁸ , John L.R. Rubenstein ⁹ , Jeffrey L. Noebels ¹ ^, ² ^, ³ , Christian Rosenmund ¹ ^, ² ^, ^* , Huda Y. Zoghbi ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ ^, ^*

Publication date PMC-release: 11 May 2011

Journal: Nature

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Summary

Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from γ-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and - 2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

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Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

Ruthie Amir, Ignatia B Van den Veyver, Mimi Wan … (1999)

Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.

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A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.

J. Guy, B. Hendrich, M. Holmes … (2001)

Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

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The story of Rett syndrome: from clinic to neurobiology.

Maria H. Chahrour, Huda Zoghbi (2007)

The postnatal neurodevelopmental disorder Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor involved in chromatin remodeling and the modulation of RNA splicing. MECP2 aberrations result in a constellation of neuropsychiatric abnormalities, whereby both loss of function and gain in MECP2 dosage lead to similar neurological phenotypes. Recent studies demonstrate disease reversibility in RTT mouse models, suggesting that the neurological defects in MECP2 disorders are not permanent. To investigate the potential for restoring neuronal function in RTT patients, it is essential to identify MeCP2 targets or modifiers of the phenotype that can be therapeutically modulated. Moreover, deciphering the molecular underpinnings of RTT is likely to contribute to the understanding of the pathogenesis of a broader class of neuropsychiatric disorders.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 30 November 2010

Publication date (Print): 11 November 2010

Publication date PMC-release: 11 May 2011

Volume: 468

Issue: 7321

Pages: 263-269

Affiliations

[1 ]Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA

[2 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

[3 ]Department of Neurology, Baylor College of Medicine, Houston, Texas, USA

[4 ]Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

[5 ]Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA

[6 ]Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA

[7 ]The Rockefeller University and Howard Hughes Medical Institute New York, New York, USA

[8 ]Center for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ontario, Canada

[9 ]Department of Psychiatry, University of California, San Francisco, California, USA

Author notes

[10]

Present address: Neurocure, Neuroscience Research Center, Charite Universitaetsmedizin Berlin, Germany

[11]

Present address: Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA

[* ]Correspondence: christian.rosenmund@ 123456charite.de (C.R.) and hzoghbi@ 123456bcm.edu (H.Y.Z.)

Author contributions 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 analyzed 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.

Article

Manuscript ID: nihpa245935

DOI: 10.1038/nature09582

PMC ID: 3057962

PubMed ID: 21068835

SO-VID: 19b66ba9-0749-4505-82b8-4bc140a27b3d

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