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

BACKGROUND

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the gene. -null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABARs, there is a group of GABARs 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 -null mice were randomly divided into four groups, receiving the extrasynaptic GABAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-]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 -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 -null mice and perhaps in people with RTT as well.