Impairment of vasoactive intestinal peptide interneurons (VIP-IN) may lead to nonseizure cognitive and behavioral comorbidities in Dravet syndrome, a study found.

The study aimed to investigate VIP-IN function at the behavioral and circuit level by conducting in vivo 2-photon calcium imaging in awake wild-type (WT) and Scn1a+/- mice.

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The researchers used AAV injections and cranial window implantation in mice to perform slice electrophysiology recordings and in vivo 2P imaging experiments. Mice were injected with AAV9 to label specific neurons and viruses for calcium imaging. Following that, cranial windows were implanted, and mice were given post-surgery treatments to promote recovery. For slice electrophysiology, mice were anesthetized and perfused with artificial cerebral spinal fluid.

Additionally, whole-cell recordings were obtained from the specific brain regions, and various electrophysiological properties of the cells were measured and analyzed. In the in vivo 2P imaging experiments, mice were habituated to head fixation and subjected to different behavioral tasks while neural activity and behavior were simultaneously recorded. Mouse behavior was analyzed using a 3-chamber social task, novel object recognition, marble burying, and elevated plus maze.

Furthermore, data analysis was performed using custom MATLAB code and Suite2p package for cell detection, normalization, and background correction, while statistical analyses were performed using linear mixed effects models and paired t-tests.

Study results showed that cholinergic modulation exacerbated the VIP-INs dysfunction by downregulating sodium ions current. Furthermore, 2P imaging results revealed that VIP-IN and pyramidal neuron activation during behavioral transition from quiet wakefulness to active running was diminished in Scn1a+/− mice, while the optogenetic activation of VIP-INs restored the pyramidal neuron activity to WT levels during the locomotion, suggesting that SST-INs remain hypoexcitable in V1 of adult Scn1a+/− mice.

Besides, it was observed that VIP-IN dysfunction is not driven by the ongoing seizure activity and does not contribute to the epilepsy phenotype of DS but instead gives rise to non-seizure disease features such as autism spectrum disorder (ASD) and intellectual disability. 

“Our data indicate that VIP-IN dysfunction may underlie the prominent comorbid ASD endophenotypes of DS independent of epilepsy,” the authors wrote. “Overall, our work demonstrates that VIP-INs represent a targetable nexus of dysfunction in DS and perhaps across neurodevelopmental disorders, highlighting the importance of developing new cell-type-specific tools and therapies,” the authors concluded. 


Goff KM, Liebergall SR, Jiang E, et al. VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome. Cell Rep. Published online June 12, 2023. doi:10.1016/j.celrep.2023.112628