Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital

Dongliang Ma, Su In Yoon, Chih Hao Yang, Guillaume Marcy, Na Zhao, Wan Ying Leong, Vinu Ganapathy, Ju Han, Antonius M J Van Dongen, Kuei Sen Hsu, Guo Li Ming, George J. Augustine, Eyleen L K Goh

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.

Original languageEnglish
Pages (from-to)477-490
Number of pages14
JournalNeurotherapeutics
Volume12
Issue number2
DOIs
Publication statusPublished - Apr 1 2015

Keywords

  • dendrites
  • GABA
  • newborn neurons
  • pentobarbital
  • Rett syndrome

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Clinical Neurology
  • Pharmacology

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