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

► The GABAA receptor is still functional in fragile X mice. ► Treatment with neuroactive steroids can rescue the audiogenic seizures in fragile X mice. ► We propose the GABAA receptor as a novel therapeutic target for fragile X syndrome. Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABAA receptors are the main inhibitory receptors in the brain and the GABAA 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 GABAA receptor in rotarod and elevated plus maze tests with fragile X mice treated with GABAA receptor agonists, the benzodiazepine diazepam and the neuroactive steroid alphaxalone. In addition, the effect of GABAA receptor activation on the audiogenic seizure activity was determined. We proved that the GABAA 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 GABAA receptor is a potential therapeutic target for fragile X syndrome.