Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible.

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1(-/-) mouse model of Fragile X syndrome (FXS). Using a go/no-go task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1(-/-) mice correlates with marked deficits in orientation tuning of principal neurons, and a decrease in the activity of parvalbumin (PV) interneurons in primary visual cortex (V1). Restoring visually evoked activity in PV cells in Fmr1(-/-) mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance. Strikingly, human subjects with FXS exhibit similar impairments in visual discrimination as Fmr1(-/-) mice. These results suggest that manipulating inhibition may help sensory processing in FXS.