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
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.
