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

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.

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Figure 1: Viaat-Mecp2 /y mice lose MeCP2 in GABA + neurons and develop stereotypies, self-injury and compulsive behaviour.
Figure 2: MeCP2 deficiency in GABAergic neurons causes several Rett syndrome-like features.
Figure 3: Loss of MeCP2 in inhibitory GABAergic neurons compromises respiration and survival.
Figure 4: MeCP2 deficiency in GABAergic neurons reduces Gad1, Gad2 and GABA levels.
Figure 5: MeCP2 deficiency in GABAergic neurons results in reduced mIPSC quantal size in cortical layer 2/3 and striatal neurons, EEG hyperexcitability and impaired hippocampal LTP.

References

  1. Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  Google Scholar 

  25. Wojcik, S. M. et al. A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron 50, 575–587 (2006)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  Google Scholar 

  29. Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006)

    CAS  Article  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)

    CAS  Article  Google Scholar 

  31. Martin, D. L. & Rimvall, K. Regulation of γ-aminobutyric acid synthesis in the brain. J. Neurochem. 60, 395–407 (1993)

    CAS  Article  Google Scholar 

  32. Tsien, J. Z. et al. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87, 1317–1326 (1996)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  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)

    CAS  Article  Google Scholar 

  38. Cui, Y. et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135, 549–560 (2008)

    CAS  Article  Google Scholar 

  39. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nature Neurosci. 10, 411–413 (2007)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  Google Scholar 

  44. Chen, W. G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003)

    ADS  CAS  Article  Google Scholar 

  45. Martinowich, K. et al. DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science 302, 890–893 (2003)

    ADS  CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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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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.

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Correspondence to Christian Rosenmund or Huda Y. Zoghbi.

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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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