Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Goff KM

PROVIDER: S-EPMC10592464 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Goff Kevin M KM Liebergall Sophie R SR Jiang Evan E Somarowthu Ala A Goldberg Ethan M EM

Cell reports 20230612 6

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<sup>+/-</sup>) 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<sup>+/-</sup> mi ...[more]

PMID: 37310860

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Project description:Recurrent seizures, which define epilepsy, are transient abnormalities in the electrical activity of the brain. The mechanistic basis of seizure initiation, and the contribution of defined neuronal subtypes to seizure pathophysiology, remains poorly understood. We performed in vivo two-photon calcium imaging in neocortex during temperature-induced seizures in male and female Dravet syndrome (Scn1a+/-) mice, a neurodevelopmental disorder with prominent temperature-sensitive epilepsy. Mean activity of both putative principal cells and parvalbumin-positive interneurons (PV-INs) was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice. Hence, PV-IN activity remains intact interictally in Scn1a+/- mice, yet exhibits decreased synchrony immediately before seizure onset. We suggest that impaired PV-IN synchronization may contribute to the transition to the ictal state during temperature-induced seizures in Dravet syndrome.SIGNIFICANCE STATEMENT Epilepsy is a common neurological disorder defined by recurrent, unprovoked seizures. However, basic mechanisms of seizure initiation and propagation remain poorly understood. We performed in vivo two-photon calcium imaging in an experimental model of Dravet syndrome (Scn1a+/- mice)-a severe neurodevelopmental disorder defined by temperature-sensitive, treatment-resistant epilepsy-and record activity of putative excitatory neurons and parvalbumin-positive GABAergic neocortical interneurons (PV-INs) during naturalistic seizures induced by increased core body temperature. PV-IN activity was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness. However, wild-type PV-INs showed progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice before seizure onset. Hence, impaired PV-IN synchronization may contribute to transition to seizure in Dravet syndrome.

Dataset Information

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

Publications

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

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