Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model.

Abstract Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABA A receptors are the main inhibitory receptors in the brain and the GABA A receptor was proposed as a novel target for treatment of the fragile X syndrome, the most frequent form of intellectual disability. This study examined the functionality of the GABA A receptor in rotarod and elevated plus maze tests with fragile X mice treated with GABA A receptor agonists, the benzodiazepine diazepam and the neuroactive steroid alphaxalone. In addition, the effect of GABA A receptor activation on the audiogenic seizure activity was determined. We proved that the GABA A receptor is still sensitive to GABAergic drugs as the sedative effect of diazepam resulted in a decreased latency time on the rotarod and alphaxalone had a clear anxiolytic effect in the elevated plus maze, decreasing the frequency of entries, the total time spent and the path length in the closed arms. We also observed that treatment with ganaxolone could rescue audiogenic seizures in Fmr1 knockout mice. These findings support the hypothesis that the GABA A receptor is a potential therapeutic target for fragile X syndrome.