Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

Kerstin Ure, Hui Lu, Wei Wang, Aya Ishida, Zhenyu Wu, Ling Jie He, Yehezkel Sztainberg, Wu Chen, Jianrong Tang, Huda Y. Zoghbi

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish
Article numbere14198
JournaleLife
Volume5
Issue numberJUN2016
DOIs
Publication statusPublished - 2016 Jun 21
Externally publishedYes

Fingerprint

Rett Syndrome
GABAergic Neurons
Restoration
Neurons
Tremor
Ataxia
Anxiety
Apraxias
Motor Skills
Seizures
Language
Hand
Phenotype
Mutation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. / Ure, Kerstin; Lu, Hui; Wang, Wei; Ishida, Aya; Wu, Zhenyu; He, Ling Jie; Sztainberg, Yehezkel; Chen, Wu; Tang, Jianrong; Zoghbi, Huda Y.

In: eLife, Vol. 5, No. JUN2016, e14198, 21.06.2016.

Research output: Contribution to journalArticle

Ure, K, Lu, H, Wang, W, Ishida, A, Wu, Z, He, LJ, Sztainberg, Y, Chen, W, Tang, J & Zoghbi, HY 2016, 'Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome', eLife, vol. 5, no. JUN2016, e14198. https://doi.org/10.7554/eLife.14198
Ure, Kerstin ; Lu, Hui ; Wang, Wei ; Ishida, Aya ; Wu, Zhenyu ; He, Ling Jie ; Sztainberg, Yehezkel ; Chen, Wu ; Tang, Jianrong ; Zoghbi, Huda Y. / Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. In: eLife. 2016 ; Vol. 5, No. JUN2016.
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