Targeting Intrinsic versus Synaptic Mechanisms in the Epileptic Brain

2021 Seed Grant
Sharon A. Swanger, Ph.D.
Virginia Tech

Pediatric epileptic encephalopathies are debilitating disorders that begin with severe and frequent seizures in infancy or early childhood. These diseases progress to complex syndromes involving not only recurring seizures but also disrupted movement, sensation, cognition, and emotional processing that persist through adulthood. The changing symptomology likely stems from abnormal brain development caused by seizures in early childhood when connections that allow communication between neurons are formed. These connections, called synapses, are essential for motor, sensory, cognitive and emotional behaviors, but proper synapse formation can be disrupted by abnormal electrical activity during seizures. Many pediatric encephalopathies are caused by mutations in voltage-gated ion channels, which are proteins that control intrinsic electrical activity of neurons and halting seizures, which are the direct result of ion channel dysfunction early in the disease. However, if abnormal synapse formation contributes to the disease, then targeting intrinsic properties of neurons may not be sufficient given that man patients are diagnosed after the critical periods of development when synapses form. Limited knowledge of how neuron communication through synapses is affected likely contributes to the lack of effective treatments. Our objective is to utilize a Dravet syndrome mouse model of pediatric epileptic encephalopathy to define how both neuronal communication and intrinsic electrical properties impact neuron function. Based on these data, we will make specific predictions regarding effective treatments targets and timing in future work. Importantly, if our findings suggest that targeting neuron communication is a viable therapeutic target this would constitute a new therapeutic direction for adolescent and adult patients with Dravet syndrome, an understudied patient population for which there is no effective treatment.

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