VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome

Kevin M. Goff; Sophie R. Liebergall; Evan Jiang; Ala Somarowthu; Ethan M. Goldberg

Cell Reports (Jun 2023)

VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome

Kevin M. Goff,
Sophie R. Liebergall,
Evan Jiang,
Ala Somarowthu,
Ethan M. Goldberg

Affiliations

Kevin M. Goff: Medical Scientist Training Program (MSTP), The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Neuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Sophie R. Liebergall: Medical Scientist Training Program (MSTP), The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Neuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Evan Jiang: Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Ala Somarowthu: Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Ethan M. Goldberg: Neuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 6
p. 112628

Abstract

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Summary: Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. We recently showed that neocortical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable in DS (Scn1a+/−) mice. Here, we investigate VIP-IN function at the circuit and behavioral level by performing in vivo 2-photon calcium imaging in awake wild-type (WT) and Scn1a+/− mice. VIP-IN and pyramidal neuron activation during behavioral transition from quiet wakefulness to active running is diminished in Scn1a+/− mice, and optogenetic activation of VIP-INs restores pyramidal neuron activity to WT levels during locomotion. VIP-IN selective Scn1a deletion reproduces core autism-spectrum-disorder-related behaviors in addition to cellular- and circuit-level deficits in VIP-IN function, but without epilepsy, sudden death, or avoidance behaviors seen in the global model. Hence, VIP-INs are impaired in vivo, which may underlie non-seizure cognitive and behavioral comorbidities in DS.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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