The GABA(A) receptor is an FMRP target with therapeutic potential in fragile X syndrome

Previous research indicates that the GABA(A)ergic 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(A)ergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABA(A) receptor subunits in the cortex and cerebellum of young Fmr1 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 FMR1 gene in an Fmr1 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 Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.