CHOP Researchers Show Epilepsy and Autism Symptoms in Dravet Syndrome May Be Caused by Separate Mechanisms

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Dravet syndrome is a severe neurodevelopmental disorder defined by treatment-resistant epilepsy and features related to autism spectrum disorder. Dravet syndrome is the most common genetic epilepsy and is caused by variants in the gene SCN1A, which codes for the protein Nav1.1, an important sodium ion channel that helps regulate the activity of seizure-suppressing inhibitory neurons in the brain.

Previously, researchers from Children’s Hospital of Philadelphia (CHOP) found that disinhibitory interneurons – interneurons that prominently inhibit other interneurons – also express Nav1.1 and were dysfunctional in an experimental model of Dravet syndrome. These interneurons express the marker vasoactive intestinal peptide (VIP), which allows for identification of the cells. 

Now, in a new study published in Cell Reports, researchers have found that dysfunction of such interneurons leads to features of cognitive impairment and autism spectrum disorder seen in Dravet syndrome, but not the seizures or epilepsy. This finding separates the cellular and circuit mechanisms underlying the epilepsy seen in this complex disorder.

The authors, led by Ethan Goldberg, MD, PhD, Director of the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP, have also found that genes implicated in autism spectrum disorder are relatively enriched in these disinhibitory interneurons. Future studies may explore these VIP interneurons as a potential therapeutic target to help patients with Dravet syndrome and other neurodevelopmental disorders.