Dataset
Goff-et-al-2023 VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome
- 1The University of Pennsylvania School of Medicine
- 2The Children's Hospital of Philadelphia
DOI: 10.12751/g-node.8s1yed BROWSE REPOSITORY BROWSE ARCHIVE DOWNLOAD ARCHIVE (ZIP 9.4 GiB)
Published 03 May. 2023 | License Creative Commons CC0 1.0 Public Domain Dedication
Description
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 investigated VIP-IN function at the circuit and behavioral level by performing in vivo 2-photon calcium imaging in awake WT and Scn1a+/- mice. VIP-IN and pyramidal neuron activation during behavioral transition from quiet wakefulness to active running was diminished in Scn1a+/- mice, and optogenetic activation of VIP-INs restored pyramidal neuron activity to WT levels during locomotion. VIP-IN selective Scn1a deletion reproduced 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 and may underlie non-seizure cognitive and behavioral comorbidities in DS.
Keywords
| Dravet syndrome | SCN1A | VIP Interneuron | Autism | Optogenetics | Two-photon imaging |References
- Goff, K. M. & Goldberg, E. M. VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome. Cell Reports (Accepted, 2023).
Funding
- NIH NINDS F31 NS111803
- NIH NINDS R01 NS110869
- The Dana Foundation David Mahoney Neuroimaging Program
- Burroughs Wellcome Fund Career Award for Medical Scientists