GlyT2-Dependent Preservation of MECP2-Expression in Inhibitory Neurons Improves Early Respiratory Symptoms but Does Not Rescue Survival in a Mouse Model of Rett Syndrome.

Swen Hülsmann,Mauricio Arnoldt,Marcus Niebert,Guillaume Mesuret,Julia Dannenberg

doi:10.3389/fphys.2016.00385

Abstract

Mutations in methyl-CpG-binding protein 2 (MECP2) gene have been shown to manifest in a neurodevelopmental disorder that is called Rett syndrome. A typical problem that occurs during development is a disturbance of breathing. To address the role of inhibitory neurons, we generated a mouse line that restores MECP2 in inhibitory neurons in the brainstem by crossbreeding a mouse line that expresses the Cre-recombinase (Cre) in inhibitory neurons under the control of the glycine transporter 2 (GlyT2, slc6a5) promotor (GlyT2-Cre) with a mouse line that has a floxed-stop mutation of the Mecp2 gene (Mecp2stop/y). Unrestrained whole-body-plethysmography at postnatal day P60 revealed a low respiratory rate and prolonged respiratory pauses in Mecp2stop/y mice. In contrast, GlyT2-Cre positive Mecp2stop/y mice (Cre+; Mecp2stop/y) showed greatly improved respiration and were indistinguishable from wild type littermates. These data support the concept that alterations in inhibitory neurons are important for the development of the respiratory phenotype in Rett syndrome.

Highlights

The neurodevelopmental disorder Rett syndrome (OMIM 312750, Rett, 1966) is caused by mutations in the gene for the methyl-CpG-binding protein 2 (MECP2)
We focused on changes of breathing, that are typically observed in the male mouse models of the Rett syndrome, regardless whether Mecp2 is knocked out in all cells (Guy et al, 2001) or only in inhibitory neurons (Chao et al, 2010)
This observation is in line with the results from a conditional Mecp2 knock out in GABAergic neurons (Chao et al, 2010)

Summary

Introduction

The neurodevelopmental disorder Rett syndrome (OMIM 312750, Rett, 1966) is caused by mutations in the gene for the methyl-CpG-binding protein 2 (MECP2). MECP2 is a X-chromosomal gene, Rett syndrome usually describes the phenotype of girls with a heterozygous mutation that occurs at a prevalence of 1/10,000–1/15,000 female births. The respiratory phenotype of female Rett syndrome patients is characterized by periods of hyperventilation alternating with prolonged periods of breathholdings causing intermittent hypoxia (Julu et al, 2001), which often resemble apneustic breathing (Kerr and Julu, 1999). These disturbances of breathing are discussed as a main cause of sudden death (Kerr et al, 1997). The male phenotype often exhibits respiratory insufficiency soon after birth with hypoventilation and prolonged apneas (Geerdink et al, 2002; Kankirawatana et al, 2006; Schüle et al, 2008)

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Conclusion