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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2023-09, Vol.111 (18), p.2863-2880.e6
• Main Authors: Kourdougli, Nazim, Suresh, Anand, Liu, Benjamin, Juarez, Pablo, Lin, Ashley, Chung, David T., Graven Sams, Anette, Gandal, Michael J., Martínez-Cerdeño, Verónica, Buonomano, Dean V., Hall, Benjamin J., Mombereau, Cédric, Portera-Cailliau, Carlos
• Format: Article
• Language: English
• Subjects: Animals; autism spectrum disorders; calcium imaging; Disease Models, Animal; Fragile X Mental Retardation Protein - genetics; Fragile X Syndrome - genetics; Humans; intellectual disability; Interneurons - physiology; Kv3.1; medial ganglionic eminence; Mice; Mice, Knockout; Neurons - metabolism; parvalbumin; Parvalbumins - genetics; Parvalbumins - metabolism; RNA-seq; tactile defensiveness; Touch; transcriptomics; two-photon
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2023.06.009

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. [Display omitted] •PV interneurons and MGE precursors are hypoactive in developing S1 of Fmr1 KO mice•PV neurons are decoupled from pyramidal cells until the second postnatal week•Lower density of PV cells in S1 of Fmr1 KO mice and in postmortem FXS human tissue•Boosting PV activity in S1 ameliorates tactile defensiveness in Fmr1 KO mice Kourdougli et al. use all-optical in vivo approaches to show that parvalbumin interneurons are hypoactive and decoupled from excitatory partners in the developing neocortex of fragile X syndrome model mice. Restoring the activity of remaining PV cells after the second postnatal week (not earlier) ameliorates sensory hypersensitivity in the mouse model.