Improvement of sensory deficits in Fragile X mice by increasing cortical interneuron activity after the critical period

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches in postnatal mouse somatosensory cortex (S1), we find that parvalbumin (PV) IN precursors are hypoactive and decoupled from excitatory neurons in Fmr1−/− mice, a model of Fragile X Syndrome (FXS). This leads to a loss of PV-INs in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1−/− mice restores PV density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering a novel allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs. ### Competing Interest Statement A.G.S., C.M. and B.J.H. are employees of H. Lundbeck A/S. who developed and provided the AG00563 compound. N.K., A.S., A.L, D.T.C., P.J., B.L. M.G., V.M.-C., D.B., and C.P.-C. declare no competing interests. A patent was filled by H. Lundbeck A/S (WO 2020/089262 A1 arylsulfonylpyrolecarboxamide derivatives as KV3 potassium channel activators).