Restoration of Mecp2 Expression in GABAergic Neurons is Sufficient to Rescue Multiple Disease Features in a Mouse Model of Rett Syndrome

Overview

Journal Elife

Specialty Biology

Date 2016 Jun 22

PMID 27328321

Citations 64

Authors

Kerstin Ure

Hui Lu

Wei Wang

Aya Ito-Ishida

Zhenyu Wu

Ling-Jie He

Yehezkel Sztainberg

Wu Chen

Jianrong Tang

Huda Y Zoghbi

Affiliations

Soon will be listed here.

Abstract

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

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