Study type: In vivo/preclinical · Status: Evidence verified by machine against declared source
VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome.
Cell reports · 2023
Study scale: We found that none of 60 VIP-Cre.Scn1a+/fl mice had seizures, and none had SUDEP prior to postnatal day 150; none of eight mice tested had temperature-induced seizures.
Abstract only: Open source record
Product or molecular entity relationships
- VIP: Exact entity relationship. Legacy citation custody associates this source with the catalog record; no product-relevance conclusion is implied.
Public plain-language summary
The published text is limited to the declared source and preserves reported uncertainty. It does not establish efficacy, safety, suitability, or evidence strength.
Research question
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.
Study design
However, it is the case that VIP-INs serve a prominent disinhibitory role linked to behavioral-state transitions and are regulators of stimulus gain control, synaptic plasticity, and learning.21–28 During transition to active behavioral states such as from quiet wakefulness to locomotion, VIP-INs are excited by ascending cholinergic and noradrenergic neuromodulation and in turn inhibit SST-INs, thereby contributing to disinhibition of local excitatory neurons.21,26,29–32 However, the effect of locomotion on neocortical activity is complex and influenced by more than VIP-INs, as many IN populations, including SST-INs, are strongly activated.33 Previous in vivo recording of PV and SST neurons in Scn1a+/− mice during the chronic phase of the disorder have not demonstrated the predicted reductions in activity level,13,34 and loss of Scn1a restricted to these cells only partially replicates the behavioral disease phenotype.18 Given a known disinhibitory role, we suspected that VIP-INs in fact may not contribute to the seizure phenotype of Scn1a+/− mice.
Participants or experimental system
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.
Study scale
We found that none of 60 VIP-Cre.Scn1a+/fl mice had seizures, and none had SUDEP prior to postnatal day 150; none of eight mice tested had temperature-induced seizures.
Intervention or exposure
Dravet syndrome (DS) is a neurodevelopmental disorder characterized by treatment-resistant epilepsy, prominent features of or formal diagnosis of ASD, cognitive impairment, and sudden unexplained death (SUDEP).5,6 DS is caused by heterozygous variants in SCN1A leading to loss of function of one copy of the voltage-gated sodium (Na+) channel α subunit Nav1.1,7,8 but a substantial gap remains between the clearly defined genetic cause of DS and a mechanistic understanding of how loss of Nav1.1 impacts brain circuits to yield this complex disorder.
Comparator
VIP-INs from Scn1a+/− mice fired at lower frequencies before application of carbachol (42 ± 2.9 vs. 34 ± 2.5 Hz, WT vs. Scn1a+/−, p = 0.04) and cholinergic modulation caused a massive decrease in excitability to near silence.
Outcomes examined
To understand how VIP-INs respond to endogenous cholinergic modulation, we first performed pharmacology experiments in acute brain slices and, surprisingly, found that application of cholinomimetics to VIP-INs in Scn1a+/− but not wild-type (WT) mice led to Na+ current downregulation that compounded existing intrinsic VIP-IN dysfunction secondary to heterozygous loss of Scn1a.
Key findings
We recently showed that neocortical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable in DS (Scn1a+/−) mice.
Limitations and uncertainty
Cerebral cortex interneurons (INs) constitute a diversity of cell types defined by electrical activity, molecular profiles, anatomy, and patterns of connectivity, and are key components of the microcircuit functions that underlie behavior.1,2 IN dysfunction is also implicated in the pathogenesis of a range of neurological and psychiatric disorders including epilepsy, schizophrenia, and autism spectrum disorder (ASD).3,4 However, it remains unclear how subtype-specific IN dysfunction contributes to disorders defined by paroxysmal events (seizures) as well as durable impairments in cognitive function.
Product relevance and evidence boundary
This record is a published study, held here with its citation and review status. It is not a statement that any catalog item is effective, safe, or suitable for any use, and nothing in it is a dose or a protocol.
Evidence verified by machine against declared source. Verification is limited to the declared source and review scope. It does not mean independent replication or establish efficacy, safety, or suitability.