Improvement of Behavioral Deficits in a Mouse Model of Fragile X Syndrome by Restoring α7 nAChR Hypofunction Associated with Aberrant Ly6H Expression

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 ( Fmr1 ^KO ) mice, an established pre-clinical model of FXS, the α7 nAChR accessory protein Ly6H is abnormally distributed, showing enrichment at the neuronal surface and mislocalization 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 Ca ²⁺ 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 Ca ²⁺ 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 improved spatial memory and reduced hyperactivity and seizure severity in adolescent Fmr1 ^KO mice. Taken together, our in vitro mechanistic findings and in vivo rescue studies implicate α7 nAChR hypofunction in FXS pathology.