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

Sien Braat, Charlotte D'Hulst, Inge Heulens, Silvia De Rubeis, Edwin Mientjes, David L Nelson, Rob Willemsen, Claudia Bagni, Debby Van Dam, Peter P De Deyn, R Frank Kooy
2018 Figshare  
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 Fmr1 knockout mice. In addition, we show that the previously reported
more » ... reported underexpression of specific subunits of the GABAA 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 GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.
doi:10.6084/m9.figshare.1342776.v3 fatcat:6xmnmrs33jal7hlfkvffdmkk7i