title: Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome.
abstract: BACKGROUND
  Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in theMECP2gene.MECP2-null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABAARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABAARs, there is a group of GABAARs found outside the synaptic cleft with the capability to produce sustained inhibition, which may be potential therapeutic targets for the control of neuronal excitability in RTT.
  
  
  METHODS
  Wild-type andMECP2-null mice were randomly divided into four groups, receiving the extrasynaptic GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP) and vehicle control, respectively. Low-dose THIP was administered to neonatal mice through lactation. RTT-like symptoms including lifespan, breathing, motor function, and social behaviors were studied when mice became mature. Changes in neuronal excitability and norepinephrine biosynthesis enzyme expression were studied in electrophysiology and molecular biology.
  
  
  RESULTS
  With no evident sedation and other adverse side effects, early-life exposure to THIP extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors ofMECP2-null mice. Such beneficial effects were associated with stabilization of locus coeruleus neuronal excitability and improvement of norepinephrine biosynthesis enzyme expression.
  
  
  CONCLUSIONS
  THIP treatment in early lives might be a therapeutic approach to RTT-like symptoms inMECP2-null mice and perhaps in people with RTT as well.
authors: Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
authors: Weiwei
authors: W
authors: Zhong
authors: Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
authors: Christopher Mychal
authors: CM
authors: Johnson
authors: Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
authors: Yang
authors: Y
authors: Wu
authors: Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
authors: Ningren
authors: N
authors: Cui
authors: Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
authors: Hao
authors: H
authors: Xing
authors: Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
authors: Shuang
authors: S
authors: Zhang
authors: Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
authors: Chun
authors: C
authors: Jiang
keywords: Behavior; Gaboxadol; Locus coeruleus; MECP2; Rett syndrome; THIP