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

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

doi:10.1186/s11689-016-9169-2

Weiwei Zhong, Hao Xing + Show 5 more

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https://doi.org/10.1186/s11689-016-9169-2

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Abstract

BackgroundRett 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.MethodsWild-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.ResultsWith 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.ConclusionsTHIP 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.

Highlights

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the Methyl CpG binding protein 2 (MECP2) gene
In MECP2-null mice, breathing disorders started at 2–3 weeks after birth, and defects in motor and social behaviors begin at 4–6 weeks [18, 19]
Consistent with our previous study showing that the daily injection of THIP in a high dose alleviates breathing abnormalities by stabilizing the neuronal activity [12], our current study shows that early-life exposure to a low dose of THIP affects multiple RTT-like symptoms

Summary

Introduction

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the MECP2 gene. Several previous studies indicate that augmenting synaptic GABA receptors (GABAARs) can alleviate RTT-like symptoms in mice. Rett syndrome (RTT) caused mostly by disruptions in the MECP2 gene is a neurodevelopmental disorder occurring in 1/10,000 live female births [1]. In MECP2-null mice, several groups of brainstem neurons including those in the locus coeruleus (LC) show increased membrane excitability. In MECP2-null mice, both GABAA and GABAB synaptic currents are reduced in LC neurons [9]. Our recent studies indicate that extrasynaptic GABAA currents are well retained in LC neurons of MECP2-null mice [12], which is encouraging as the extrasynaptic GABA receptors (GABAARs) may provide an alternative pharmaceutical target to relieve the excessive neuronal excitability and its associated RTT symptoms. We have found that the extrasynaptic GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]

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