Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes (original) (raw)

References

1. Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007)
   Article CAS Google Scholar
2. Lam, C. W. et al. Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J. Med. Genet. 37, e41 (2000)
   Article CAS Google Scholar
3. Klauck, S. M. et al. A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. Am. J. Hum. Genet. 70, 1034–1037 (2002)
   Article CAS Google Scholar
4. Cohen, D. et al. MECP2 mutation in a boy with language disorder and schizophrenia. Am. J. Psychiatry 159, 148–149 (2002)
   Article Google Scholar
5. Carney, R. M. et al. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr. Neurol. 28, 205–211 (2003)
   Article Google Scholar
6. Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999)
   Article CAS Google Scholar
7. Hagberg, B., Aicardi, J., Dias, K. & Ramos, O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann. Neurol. 14, 471–479 (1983)
   Article CAS Google Scholar
8. Weese-Mayer, D. E. et al. Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome. Pediatr. Res. 60, 443–449 (2006)
   Article Google Scholar
9. Weese-Mayer, D. E. et al. Autonomic dysregulation in young girls with Rett syndrome during nighttime in-home recordings. Pediatr. Pulmonol. 43, 1045–1060 (2008)
   Article Google Scholar
10. Deidrick, K. M., Percy, A. K., Schanen, N. C., Mamounas, L. & Maria, B. L. Rett syndrome: pathogenesis, diagnosis, strategies, therapies, and future research directions. J. Child Neurol. 20, 708–717 (2005)
    Article Google Scholar
11. Jedele, K. B. The overlapping spectrum of Rett and Angelman syndromes: a clinical review. Semin. Pediatr. Neurol. 14, 108–117 (2007)
    Article Google Scholar
12. Hagberg, B. Clinical manifestations and stages of Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 8, 61–65 (2002)
    Article Google Scholar
13. Neul, J. L. et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 70, 1313–1321 (2008)
    Article CAS Google Scholar
14. Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nature Genet. 27, 322–326 (2001)
    Article CAS Google Scholar
15. Chen, R. Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nature Genet. 27, 327–331 (2001)
    Article CAS Google Scholar
16. Shahbazian, M. et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35, 243–254 (2002)
    Article CAS Google Scholar
17. Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006)
    Article CAS Google Scholar
18. Fyffe, S. L. et al. Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59, 947–958 (2008)
    Article CAS Google Scholar
19. Samaco, R. C. et al. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc. Natl Acad. Sci. USA 106, 21966–21971 (2009)
    Article ADS CAS Google Scholar
20. Adachi, M., Autry, A. E., Covington, H. E., III & Monteggia, L. M. MeCP2-mediated transcription repression in the basolateral amygdala may underlie heightened anxiety in a mouse model of Rett syndrome. J. Neurosci. 29, 4218–4227 (2009)
    Article CAS Google Scholar
21. Ballas, N., Lioy, D. T., Grunseich, C. & Mandel, G. Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nature Neurosci. 12, 311–317 (2009)
    Article CAS Google Scholar
22. Maezawa, I., Swanberg, S., Harvey, D., LaSalle, J. M. & Jin, L. W. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J. Neurosci. 29, 5051–5061 (2009)
    Article CAS Google Scholar
23. Gong, S. et al. Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs. J. Neurosci. 27, 9817–9823 (2007)
    Article CAS Google Scholar
24. Chaudhry, F. A. et al. The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J. Neurosci. 18, 9733–9750 (1998)
    Article CAS Google Scholar
25. Wojcik, S. M. et al. A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron 50, 575–587 (2006)
    Article CAS Google Scholar
26. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001)
    Article CAS Google Scholar
27. Samaco, R. C. et al. A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum. Mol. Genet. 17, 1718–1727 (2008)
    Article CAS Google Scholar
28. Swerdlow, N. R., Geyer, M. A. & Braff, D. L. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl.) 156, 194–215 (2001)
    Article CAS Google Scholar
29. Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006)
    Article CAS Google Scholar
30. Kohwi, M. et al. A subpopulation of olfactory bulb GABAergic interneurons is derived from _Emx1_- and _Dlx5/6_-expressing progenitors. J. Neurosci. 27, 6878–6891 (2007)
    Article CAS Google Scholar
31. Martin, D. L. & Rimvall, K. Regulation of γ-aminobutyric acid synthesis in the brain. J. Neurochem. 60, 395–407 (1993)
    Article CAS Google Scholar
32. Tsien, J. Z. et al. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87, 1317–1326 (1996)
    Article CAS Google Scholar
33. Chao, H. T., Zoghbi, H. Y. & Rosenmund, C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007)
    Article CAS Google Scholar
34. Dani, V. S. & Nelson, S. B. Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett Syndrome. J. Neurosci. 29, 11263–11270 (2009)
    Article CAS Google Scholar
35. Dani, V. S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005)
    Article ADS CAS Google Scholar
36. Medrihan, L. et al. Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome. J. Neurophysiol. 99, 112–121 (2008)
    Article CAS Google Scholar
37. Zhang, L., He, J., Jugloff, D. G. & Eubanks, J. H. The MeCP2-null mouse hippocampus displays altered basal inhibitory rhythms and is prone to hyperexcitability. Hippocampus 18, 294–309 (2008)
    Article CAS Google Scholar
38. Cui, Y. et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135, 549–560 (2008)
    Article CAS Google Scholar
39. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nature Neurosci. 10, 411–413 (2007)
    Article CAS Google Scholar
40. Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007)
    Article ADS CAS Google Scholar
41. Chadman, K. K. et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res. 1, 147–158 (2008)
    Article Google Scholar
42. Skene, P. J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010)
    Article CAS Google Scholar
43. Yasui, D. H. et al. Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc. Natl Acad. Sci. USA 104, 19416–19421 (2007)
    Article ADS CAS Google Scholar
44. Chen, W. G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003)
    Article ADS CAS Google Scholar
45. Martinowich, K. et al. DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science 302, 890–893 (2003)
    Article ADS CAS Google Scholar
46. Akbarian, S. et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch. Gen. Psychiatry 52, 258–266 (1995)
    Article CAS Google Scholar
47. Fatemi, S. H. et al. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol. Psychiatry 52, 805–810 (2002)
    Article CAS Google Scholar
48. Addington, A. M. et al. GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol. Psychiatry 10, 581–588 (2005)
    Article CAS Google Scholar
49. Lundorf, M. D. et al. Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 135B, 94–101 (2005)
    Article CAS Google Scholar
50. Fatemi, S. H., Stary, J. M., Earle, J. A., Araghi-Niknam, M. & Eagan, E. GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr. Res. 72, 109–122 (2005)
    Article Google Scholar

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Acknowledgements

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.).

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Author notes

1. Mingshan Xue & Christian Rosenmund
   Present address: 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.).,

Authors and Affiliations

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, 77030, Texas, 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, 77030, Texas, USA
   Jong Yoo, Jeffrey L. Noebels & Huda Y. Zoghbi
4. Department of Pediatrics, Baylor College of Medicine, Houston, 77030, Texas, 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, 77030, Texas, USA
   Jeffrey L. Neul, Hui-Chen Lu & Huda Y. Zoghbi
6. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, 77030, Texas, USA
   Huda Y. Zoghbi
7. The Rockefeller University and Howard Hughes Medical Institute, New York, 10021, New York, USA
   Shiaoching Gong & Nathaniel Heintz
8. Department of Biology, Center for Advanced Research in Environmental Genomics, University of Ottawa, Ontario K1N 6N5, Canada,
   Marc Ekker
9. Department of Psychiatry, University of California, San Francisco, 94158, California, USA
   John L. R. Rubenstein

Authors

1. Hsiao-Tuan Chao
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2. Hongmei Chen
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3. Rodney C. Samaco
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4. Mingshan Xue
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5. Maria Chahrour
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6. Jong Yoo
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7. Jeffrey L. Neul
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8. Shiaoching Gong
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9. Hui-Chen Lu
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10. Nathaniel Heintz
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11. Marc Ekker
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12. John L. R. Rubenstein
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13. Jeffrey L. Noebels
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14. Christian Rosenmund
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15. Huda Y. Zoghbi
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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 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.

Corresponding authors

Correspondence toChristian Rosenmund or Huda Y. Zoghbi.

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The authors declare no competing financial interests.

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Chao, HT., Chen, H., Samaco, R. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature 468, 263–269 (2010). https://doi.org/10.1038/nature09582

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• Received: 12 January 2010
• Accepted: 15 October 2010
• Published: 10 November 2010
• Issue Date: 11 November 2010
• DOI: https://doi.org/10.1038/nature09582