A role for glia in the progression of Rett's syndrome - PubMed (original) (raw)
A role for glia in the progression of Rett's syndrome
Daniel T Lioy et al. Nature. 2011.
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). Although MeCP2 is expressed in most tissues, loss of MeCP2 expression results primarily in neurological symptoms. Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons. 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 fashion. 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.
Figures
Figure 1
a, Efficiencies of Mecp2 re-expression. The numbers above the bars indicate total number of cells counted. b, Genomic PCR analysis of non-recombined (Stop; 4.3 kb) and recombined amplicons (1.29 kb) of FACS-sorted NeuN+ and NeuN- cells from the whole brain of a TAM-treated Mecp2Stop/y-hGFAPcreT2 mouse. Genomic DNA was prepared from 500,000 cells per group. The wild-type (1.25 kb) Mecp2 amplicon is indicated. The β-actin promoter amplicon shows that similar amounts of DNA were present in the reactions. c, Fluorescence-intensity histogram derived from individual hippocampal pyramidal neurons in tissue sections. Cy2 immunofluorescence intensities of nuclear MeCP2 protein are indicated above the line; DAPI fluorescence intensities of the same neurons are indicated below the line. ALU, arbitrary linear units. n = 3 mice per genotype and 100 cells per mouse.
Figure 2
a, Representative activity in a home-cage-like setting. Duration interval, 5 min. Scale bars indicate 7 inches. b, Locomotor activity histograms in a home-cage-like setting. Duration interval, 10 min. c, Locomotor activity histograms in an open field. Duration, 20 min. d, Time spent in centre of an open field. e, Time spent in open portions of an elevated zero maze. Mice aged 3-4 months. *P < 0.05, **P < 0.01, ***P < 0.001. All error bars indicate s.e.m. The number of mice analysed is indicated above each bar. b-e, Genotypes as in a.
Figure 3
a, Representative plethysmographic recordings from a female RTT patient (modified from ref. 22) and an Mecp2Stop/y-hGFAPcreT2 mouse and control. The two middle traces are from the same Mecp2Stop/y-hGFAPcreT2 mouse before and 62 days after TAM treatment (Supplementary Fig. 7c, trace 3). b, Respiratory irregularity scores and apnoea rates for male mice. c, Same as in b except for female mice. Mice showing at least 1 apnoea per hour were considered for apnoea rates. All error bars indicate s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. NS, not significant. The number of mice analysed is indicated above each bar.
Figure 4
a, Somal diameters of indicated neurons. Control, hGFAPcreT2 + TAM. b, Representative traces of silver-impregnated hippocampal CA1 neurons from male mice aged 3-4 months. c, Number of silver-impregnated CA1 apical branches in male mice. Control, Mecp2+/y + TAM. d, Representative images of Nissl-stained neurons immunolabelled for VGLUT1 from medulla oblongata. Scale bar: 10 μm (b); 2 μm (d). e, Number of VGLUT1+ puncta associated with neuronal cell bodies from the medulla oblongata. All error bars indicate s.e.m. ***P < 0.001. NS, not significant. The number of analysed cells is indicated above each bar.
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References
- Chahrour M, Zoghbi HY. Neuron. 2007;56:422–37. - PubMed
- Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Hum. Mol. Genet. 2002;11:115. - PubMed
- Guy J, Hendrich B, Holmes M, Martin JE, Bird A. Nat. Genet. 2001;3:322–6. - PubMed
- Chen RZ, Akbarian S, Tudor M, Jaenisch R. Nat. Genet. 2001;3:327–31. - PubMed
- Kishi N, Macklis JD. Mol. Cell Neurosci. 2004;27:306–21. - PubMed
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