Abstract
Rett’s syndrome (RTT) is an X-chromosome-linked autism spectrum disorder caused by loss of function of the transcription factor methyl-CpG-binding protein 2 (MeCP2)1. Although MeCP2 is expressed in most tissues2, loss of MeCP2 expression results primarily in neurological symptoms1,3,4. Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons2,4,5,6,7,8,9,10. Although defective neurons clearly underlie the aberrant behaviours, we and others showed recently that the loss of MECP2 from glia negatively influences neurons in a non-cell-autonomous fashion11,12,13. Here we show that in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice. Furthermore, restoration of MeCP2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Our study shows that glia, like neurons, are integral components of the neuropathology of RTT, and supports the targeting of glia as a strategy for improving the associated symptoms.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007)
Shahbazian, M. D., Antalffy, B., Armstrong, D. L. & Zoghbi, H. Y. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum. Mol. Genet. 11, 115 (2002)
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)
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)
Kishi, N. & Macklis, J. D. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol. Cell. Neurosci. 27, 306–321 (2004)
McGill, B. E. et al. Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 103, 18267–18272 (2006)
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)
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)
Luikenhuis, S., Giacometti, E., Beard, C. F. & Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc. Natl Acad. Sci. USA 101, 6033–6038 (2004)
Chao, H. T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010)
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)
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)
Maezawa, I. & Jin, L. W. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J. Neurosci. 30, 5346–5356 (2010)
Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007)
Hirrlinger, P. G., Scheller, A., Braun, C., Hirrlinger, J. & Kirchhoff, F. Temporal control of gene recombination in astrocytes by transgenic expression of the tamoxifen-inducible DNA recombinase variant CreERT2. Glia 54, 11–20 (2006)
Brenner, M., Kisseberth, W. C., Su, Y., Besnard, F. & Messing, A. GFAP promoter directs astrocyte-specific expression in transgenic mice. J. Neurosci. 14, 1030–1037 (1994)
Chow, L., Zhang, J. & Baker, S. J. Temporal control of gene recombination in astrocytes by transgenic expression of the tamoxifen-inducible DNA recombinase variant CreERT2. Transgenic Res. 17, 919–928 (2008)
Casper, K. B., Jones, K. & McCarthy, K. D. Characterization of astrocyte-specific conditional knockouts. Genesis 45, 292–299 (2007)
Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nature Biotechnol. 27, 59–65 (2008)
Stearns, N. A. et al. Behavioral and anatomical abnormalities in Mecp2 mutant mice: A model for Rett syndrome. Neuroscience 146, 907–921 (2007)
Pelka, G. J. et al. Brain Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice. 129, 887–898 (2006)
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)
Viemari, J. et al. Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice. J. Neurosci. 25, 11521–11530 (2005)
Bauman, M. L., Kemper, T. L. & Arin, D. M. Pervasive neuroanatomic abnormalities of the brain in three cases of Rett’s syndrome. Neurology 45, 1581–1586 (1995)
Armstrong, D. D. Neuropathology of Rett syndrome. J. Child Neurol. 20, 747–753 (2005)
Chao, H. T., Zoghbi, H. Y. & Rosenmund, C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007)
Marchetto, M. L. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010)
Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009)
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. Psychol. 59, 468–476 (2006)
Acknowledgements
We thank P. Brehm, R. H. Goodman, C. Bond, M. McGinley and C. Mandel-Brehm for discussions; P. Micha, J. Eng, S. Knopp and T. Shaffer for technical support; and M. Murtha for generating the CBA/CMV-MECP2 construct. ViraPur, LLC generated the AAV9 virus. The work was supported by grants from the National Institutes of Health (G.M. and N.B.), International Rett Syndrome Foundation (N.B. and J.M.B.), Rett Syndrome Research Trust (G.M. and B.K.K.), Oregon Brain Institute (D.T.L.), and OHSU Cell and Developmental Biology Training Program (D.T.L.). G.M. is an Investigator of the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Contributions
D.T.L., S.K.G., J.R., J.M.B., N.B. and G M. designed the astrocyte knockout and rescue experiments. B.K.K. and K.D.F. helped design the AAV9 experiments. D.T.L., S.K.G., C.E.M. and J.M.B. performed the experiments. P.G.H. and F.K. provided the hGFAPcreT2 transgenic mice. D.T.L., S.K.G., N.B. and G.M. wrote the manuscript with input from the other co-authors.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Figures
The file contains Supplementary Figures 1-10 with legends. (PDF 24597 kb)
Supplementary Movie 1
The movie shows A symptomatic oil-treated Mecp2Stop/y-hGFAPcreT2 mouse at 13 weeks of age (see Fig. S10A for phenotype scoring of this mouse). (MOV 1948 kb)
Supplementary Movie 2
The movie shows A TAM-treated Mecp2Stop/y-hGFAPcreT2 mouse at seven months of age (see Fig. S10B for phenotype scoring of this mouse). (MOV 1938 kb)
Rights and permissions
About this article
Cite this article
Lioy, D., Garg, S., Monaghan, C. et al. A role for glia in the progression of Rett’s syndrome. Nature 475, 497–500 (2011). https://doi.org/10.1038/nature10214
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature10214
This article is cited by
-
Astrocytes in human central nervous system diseases: a frontier for new therapies
Signal Transduction and Targeted Therapy (2023)
-
Extension of the Lifespan of a Mouse Model of Rett Syndrome by Intracerebroventricular Delivery of MECP2
Neuroscience Bulletin (2023)
-
AQP4 labels a subpopulation of white matter-dependent glial radial cells affected by pediatric hydrocephalus, and its expression increased in glial microvesicles released to the cerebrospinal fluid in obstructive hydrocephalus
Acta Neuropathologica Communications (2022)
-
Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex
Nature Communications (2022)
-
Astrocytic Gap Junctions Contribute to Aberrant Neuronal Synchronization in a Mouse Model of MeCP2 Duplication Syndrome
Neuroscience Bulletin (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.