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Many studies have reported brain region and age-dependent alterations in the expression of several subunits of the GABA A  receptor in  Fmr1  KO mice. GABA A  receptors are located synaptic and extrasynaptic with differential subunit compositions and characteristics. Interestingly, the activity of many subunits of the GABA A  receptor is amendable by differential pharmacological treatment. The purpose of this review is to summarize the expression of GABA A  receptor subunits in different brain regions of  Fmr1  KO mice across different ages. The decreased expression of the synaptic α2 subunit in juvenile, and the decreased expression of the extrasynaptic δ subunit in both juvenile and adult  Fmr1  KO mice, are among the most consistent abnormalities reported. Both subunits are suitable for treatment and currently available compounds are discussed in this review along with their therapeutic potential. Pharmacological treatment targeting specific subunits of the GABA A  receptor has shown selective improvements in fragile X syndrome. To our knowledge, combinatorial therapies targeting multiple subunits of the GABA A  receptor have not been explored. We here argue that such a combination therapy could induce a synergistic effect to ameliorate the clinical symptoms of fragile X syndrome.

Therapeutic potential of GABA A receptor subunit expression abnormalities in fragile X syndrome