title: Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital.
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.
authors.affiliation: Programme in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ma
authors.forename: Su-In
authors.initials: SI
authors.lastname: Yoon
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Yang
authors.forename: Guillaume
authors.initials: G
authors.lastname: Marcy
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.forename: Wan-Ying
authors.initials: WY
authors.lastname: Leong
authors.forename: Vinu
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Ju
authors.initials: J
authors.lastname: Han
authors.forename: Antonius M J
authors.initials: AM
authors.lastname: Van Dongen
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
authors.forename: Guo-Li
authors.initials: GL
authors.lastname: Ming
authors.forename: George J
authors.initials: GJ
authors.lastname: Augustine
authors.forename: Eyleen L K
authors.initials: EL
authors.lastname: Goh
mesh_terms: D000759:Adjuvants, Anesthesia / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009415:Nerve Net / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D016704:Synapsins / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000759:Adjuvants, Anesthesia; D051783:Methyl-CpG-Binding Protein 2; D026941:Sodium Channel Blockers; D016704:Synapsins; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital