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

Kourdougli, N.; Suresh, A.; Liu, B.; Juarez, P.; Lin, A.; Chung, D. T.; Graven Sams, A.; Gandal, M.; Martinez-Cerdeno, V.; Buonomano, D.; Hall, B.; Mombereau, C.; Portera-Cailliau, C.

doi:10.1101/2022.05.17.492368

bioRxiv · 10.1101/2022.05.17.492368

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

Kourdougli, N.·Suresh, A.·Liu, B.·Juarez, P.·Lin, A.·Chung, D. T.·Graven Sams, A.·Gandal, M.·Martinez-Cerdeno, V.·Buonomano, D.·Hall, B.·Mombereau, C.·Portera-Cailliau, C.

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Abstract

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.

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Kourdougli, N., Suresh, A., Liu, B., Juarez, P., Lin, A., Chung, D. T., Graven Sams, A., Gandal, M., Martinez-Cerdeno, V., Buonomano, D., Hall, B., Mombereau, C., Portera-Cailliau, C.. 2022-05-18. Improvement of sensory deficits in Fragile X mice by increasing cortical interneuron activity after the critical period. https://doi.org/10.1101/2022.05.17.492368

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