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Journal of Neurodevelopmental Disorders
Published in: Journal of Neurodevelopmental Disorders 1/2016

Open Access 01-12-2016 | Research

Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome

Authors: Weiwei Zhong, Christopher Mychal Johnson, Yang Wu, Ningren Cui, Hao Xing, Shuang Zhang, Chun Jiang

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2016

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Abstract

Background

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the MECP2 gene. 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 and MECP2-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 of MECP2-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 in MECP2-null mice and perhaps in people with RTT as well.
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Metadata
Title
Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome
Authors
Weiwei Zhong
Christopher Mychal Johnson
Yang Wu
Ningren Cui
Hao Xing
Shuang Zhang
Chun Jiang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neurodevelopmental Disorders / Issue 1/2016
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI
https://doi.org/10.1186/s11689-016-9169-2

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