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.
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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.
The authors declare no competing financial interests.
The file contains Supplementary Figures 1-10 with legends. (PDF 24597 kb)
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)
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)
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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
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