Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABA(A) Receptors

Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABA(A)R) seems to be also involved regarding the therapeutic basis for hyperekplexia using benzodiazepines, which target GABA(A)Rs but not GlyRs. Here, we show that the function of GABA(A)Rs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be mediated by interaction between GABA(A)R and mutant GlyR. The GABA(A)R dysfunction was caused only by mutant GlyR consisting of homomeric α(1) subunits, which locate primarily at pre- and extra-synaptic sites. In addition, the rescue effects of diazepam were attenuated by Xli-093, which specifically blocked diazepam-induced potentiation on α(5)-containing GABA(A)R, a major form of pre- and extra-synaptic GABA(A)R in the brainstem. Thus, our results suggest that the pre- and extra-synaptic GABA(A)Rs could be a potential therapeutic target for hyperekplexia disease caused by GlyR mutations.