Decreased expression of the GABAA receptor in fragile X syndrome

After our initial discovery of under expression of the GABAA receptor δ subunit in a genome wide screening for differentially expressed mRNAs in brain of fragile X mice, a validated model for fragile X mental retardation syndrome, we analyzed expression of the 17 remaining subunits of the GABAA receptor using real-time PCR. We confirmed nearly 50% under expression of the δ subunit and found a significant 35%–50% reduction in expression of 7 additional subunit mRNAs, namely α1, α3, and α4, β1 and β2 and γ1 and γ2, in fragile X mice compared to wild-type littermates. In concordance with previous results, under expression was found in cortex, but not in cerebellum. Moreover, decreased expression of specific GABAA receptor subunits in fragile X syndrome seems to be an evolutionary conserved hallmark since in the fragile X fly (Drosophila melanogaster) model we also found almost 50% under expression of all 3 subunits which make up the invertebrate GABA receptor, namely Grd, Rdl and Lcch3. In addition, we demonstrated a direct correlation between the amount of dFmrp and the expression of the GABA receptor subunits Rdl and Grd. Our results add evidence to previous observations of an altered GABAergic system in fragile X syndrome. Because GABAA receptors are the major inhibitory receptors in brain, involved in anxiety, depression, insomnia, learning and memory and epilepsy, processes also disturbed in fragile X patients, the well described GABAA receptor pharmacology might open new powerful opportunities for treatment of the behavioral and epileptic phenotype associated with fragile X syndrome.