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Mice that are deficient in the transcription factor methyl-CpG-binding protein 2 (MeCP2) have a depressed hypercapnic ventilatory response (HCVR). The expression of MeCP2 can be selectively removed from astrocytes or neurons, thus offering a tool to dissect the role of this transcription factor in astrocytes from that in neurons. Studies were carried out in the progeny of mice that were a cross between those harboring a tamoxifen (TAM)-inducible Cre recombinase transgene driven by the human astrocytic glial fibrillary acidic protein (hGFAP) promoter, or Cre recombinase under control of the synapsin promoter, with mice containing a Cre-excisable exon III in the Mecp2 gene. The TAM-conditional excision of the Mecp2 exon allowed the respiratory CO2 response to be studied in the same animals before and after selective depletion of MeCP2 in astrocytes. Immunohistochemistry showed that following TAM treatment only ∼20% of GFAP-labeled cells in the retrotrapazoid nucleus and in the raphé magnus were positive for MeCP2. The slope of the relative increase in minute ventilation as a function of 1, 3, and 5% inspired CO2 was depressed in mice with depleted astrocyte MeCP2 compared with wild-type littermates. In contrast, selective depletion of MeCP2 in neurons did not significantly affect slope. While neurons which constitute the respiratory network ultimately determine the ventilatory response to CO2, this study demonstrates that loss of MeCP2 in astrocytes alone is sufficient to result in a dramatic attenuation of the HCVR. We propose that the glial contribution to HCVR is under the control of the MeCP2 gene., (Copyright © 2015 the American Physiological Society.)

De novo mutations in the X-linked gene encoding the transcription factor methyl-CpG binding protein 2 (MECP2) are the most frequent cause of the neurological disorder Rett syndrome (RTT). Hemizygous males usually die of neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss of purposeful hand motions and speech, and motor abnormalities, which appear after a period of apparently normal development. Most studies have focused on male mouse models because of the shorter latency to and severity in symptoms, yet how well these mice mimic the disease in affected females is not clear. Very few therapeutic treatments have been proposed for females, the more gender-appropriate model. Here, we show that self-complementary AAV9, bearing MeCP2 cDNA under control of a fragment of its own promoter (scAAV9/MeCP2), is capable of significantly stabilizing or reversing symptoms when administered systemically into female RTT mice. To our knowledge, this is the first potential gene therapy for females afflicted with RTT.

Rett syndrome (RTT) is an autism spectrum disorder with an incidence of ~1:10,000 females (reviewed in Bird, 2008; Chahrour et al., 2007; Francke, 2006). Affected individuals are apparently normal at birth. Between 6-18 months of age, however, RTT patients begin to exhibit deceleration of head growth, replacement of purposeful hand movements with stereotypic hand wringing, loss of speech, social withdrawal and other autistic features. RTT is caused by loss of function mutations in the gene that encodes methyl-CpG-binding protein 2 (Mecp2) (Amir et al., 1999), a transcriptional repressor that targets genes essential for neuronal survival, dendritic growth, synaptogenesis, and activity dependent plasticity. MECP2 is X-linked, and males die soon after birth. Included in the RTT phenotype are cardiorespiratory disorders involving the autonomic nervous system. The respiratory disorders, including the roles of bioaminergic and brain derived neurotrophic factor (BDNF) signaling in the respiratory pathophysiology of RTT have been recently reviewed (Bissonnette et al., 2007a; Ogier et al., 2008; Katz et al., 2009). Here we will cover the work on RTT regarding respiration that has appeared since 2009 as well as cardiovascular abnormalities., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The neurodevelopmental disorder Rett syndrome (RTT) is caused by sporadic mutations in the transcriptional factor methyl-CpG-binding protein 2 (MeCP2). Although it is thought that the primary cause of RTT is cell autonomous, resulting from a lack of functional MeCP2 in neurons, whether non-cell autonomous factors contribute to the disease is unknown. We found that the loss of MeCP2 occurs not only in neurons but also in glial cells of RTT brains. Using an in vitro co-culture system, we found that mutant astrocytes from a RTT mouse model, and their conditioned medium, failed to support normal dendritic morphology of either wild-type or mutant hippocampal neurons. Our studies suggest that astrocytes in the RTT brain carrying MeCP2 mutations have a non-cell autonomous effect on neuronal properties, probably as a result of aberrant secretion of soluble factor(s).

Both increases and decreases in methyl CpG-binding protein 2 (MeCP2) levels cause neurodevelopmental defects. We found that MeCP2 translation is regulated by microRNA 132 (miR132). Block of miR132-mediated repression increased MeCP2 and brain-derived neurotrophic factor (BDNF) levels in cultured rat neurons and the loss of MeCP2 reduced BDNF and miR132 levels in vivo. This feedback loop may provide a mechanism for homeostatic control of MeCP2 expression.