Previous research indicates that the GABAAergic 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 GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAa 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 GABAa 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 GABAa receptor mRNAs. Finally, positive allosteric modulation of GABAa receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmrl knockout mice, emphasizing the therapeutic potential of the receptor.

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Keywords Fmrl knockout mouse, FMRP mRNA target, Fragile X syndrome, GABAA receptor, Ganaxolone, Targeted therapy
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Journal Cell Cycle
Braat, S, D’Hulst, C, Heulens, I, de Rubeis, S, Mientjes, E.J, Nelson, D.L, … Kooy, R.F. (2015). The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. Cell Cycle, 14(18), 2985–2995. doi:10.4161/15384101.2014.989114