The GABA_A receptor is an FMRP target with therapeutic potential in fragile X syndrome

Previous research indicates that the GABA_Aergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABA_Aergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABA_a receptor subunits in the cortex and cerebellum of young Fmrl knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABA_a receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMRl gene in an Fmrl knockout background. Moreover, we demonstrate that FMRP directly binds several GABA_a receptor mRNAs. Finally, positive allosteric modulation of GABA_a receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmrl knockout mice, emphasizing the therapeutic potential of the receptor.