Abstract
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and often accompanied with debilitating pathologies including seizures and hyperactivity. FXS arises from a trinucleotide repeat expansion in the 5' UTR of the FMR1 gene that silences expression of the RNA-binding protein FMRP. Despite progress in understanding FMRP functions, the identification of effective therapeutic targets has lagged and at present there are no viable treatment options. Here we identify the α7 nicotinic acetylcholine receptor (nAChR) as candidate target for intervention in FXS. In the early postnatal hippocampus of Fmr1 knockout (KO) mice, an established pre-clinical model of FXS, the α7 nAChR accessory protein Ly6H is abnormally enriched at the neuronal surface and mislocalized in dendrites. Ly6H, a GPI-anchored protein, binds α7 nAChRs with high affinity and can limit α7 nAChR surface expression and signaling. We find that α7 nAChR-evoked Ca2+ responses are dampened in immature glutamatergic and GABAergic Fmr1 KO neurons compared to wild type. Knockdown of endogenous Ly6H in Fmr1 KO neurons is sufficient to rescue dampened α7 nAChR Ca2+ responses in vitro, providing evidence of a cell-autonomous role for Ly6H aberrant expression in α7 nAChR hypofunction. In line with intrinsic deficits in α7 nAChR activity in Fmr1 KO neurons, in vivo administration of the α7 nAChR-selective positive allosteric modulator PNU-120596 reduced hyperactivity and seizure severity in adolescent Fmr1 KO mice. Our mechanistic studies together with evidence of the in vivo efficacy of α7 nAChR augmentation implicate α7 nAChR hypofunction in FXS pathology.