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.
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| http://dx.doi.org/10.1016/j.celrep.2023.112628 | DOI Listing |
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Article Synopsis
- Dravet Syndrome (DS) is a severe epilepsy in children that increases the risk of Sudden Unexpected Death in Epilepsy (SUDEP), often linked to mutations in a specific gene affecting both the brain and heart.
- Research using a DS mouse model revealed significant sex-specific changes in cardiac mitochondrial function, with male mice showing reduced respiratory capacity and increased vulnerability to arrhythmias.
- The study highlights that males are more susceptible to these cardiac issues compared to females, suggesting that therapeutic approaches for SUDEP risk in DS should take sex differences into account.
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