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

Autor:	Kourdougli N; Department of Neurology, UCLA, Los Angeles, CA, USA., Suresh A; Department of Neurology, UCLA, Los Angeles, CA, USA., Liu B; Department of Neurology, UCLA, Los Angeles, CA, USA., Juarez P; Department of Pathology, UC Davis, Davis, CA, USA., Lin A; Department of Neurology, UCLA, Los Angeles, CA, USA., Chung DT; Department of Neurology, UCLA, Los Angeles, CA, USA., Graven Sams A; Lundbeck A/S H, Ottiliavej 9, 2500 Copenhagen, Denmark., Gandal MJ; Department of Psychiatry, UCLA, Los Angeles, CA, USA., Martínez-Cerdeño V; Department of Pathology, UC Davis, Davis, CA, USA; MIND Institute, UC Davis, Davis, CA, USA., Buonomano DV; Department of Neurology, UCLA, Los Angeles, CA, USA; Department of Psychology, UCLA, Los Angeles, CA, USA., Hall BJ; Lundbeck A/S H, Ottiliavej 9, 2500 Copenhagen, Denmark., Mombereau C; Lundbeck A/S H, Ottiliavej 9, 2500 Copenhagen, Denmark., Portera-Cailliau C; Department of Neurology, UCLA, Los Angeles, CA, USA; Department of Neurobiology, UCLA, Los Angeles, CA, USA. Electronic address: cpcailliau@mednet.ucla.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2023 Sep 20; Vol. 111 (18), pp. 2863-2880.e6. Date of Electronic Publication: 2023 Jul 13.
DOI:	10.1016/j.neuron.2023.06.009
Abstrakt:	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, we find that parvalbumin (PV) INs and their immature precursors are hypoactive and transiently decoupled from excitatory neurons in postnatal mouse somatosensory cortex (S1) of Fmr1 KO mice, a model of fragile X syndrome (FXS). This leads to a loss of parvalbumin INs (PV-INs) in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1 KO mice restores PV-IN density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering an 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 Interests: Declaration of interests A.G.S., C.M., and B.J.H. are employees of H. Lundbeck A/S, who developed the AG00563 compound. A patent was filled by H. Lundbeck A/S (WO 2020/089262). (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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