Investigating spreading depolarization as a central mechanism of electroconvulsive therapy in a mouse neurodevelopmental model - PROJECT SUMMARY Neurodevelopmental disorders (NDDs) cause profound neuropsychiatric abnormalities including depression, psychosis, self-injury, and autism spectrum disorder, which frequently co-occur with epilepsy. These symptoms are often medication-resistant and increase risk of premature mortality. Exemplifying this complexity, Dravet Syndrome (DS) is caused by mutations in the gene SCN1A, encoding Nav1.1 sodium channels, leading to early- onset epilepsy and elevated risk of sudden death, depression, aggression, and autism. Current DS treatments remain largely palliative. Electroconvulsive therapy (ECT) represents the gold standard intervention when medications fail, providing rapid relief across neuropsychiatric symptom domains including severe depression, status epilepticus, psychosis, catatonia, and repetitive self-injury. ECT demonstrates particular efficacy in NDDs but remains underutilized and its mechanism is poorly understood. I recently reported that ECT induces a previously hidden brain event, cortical spreading depolarization (CSD), immediately post-seizure. CSD is an inhibitory wave that resets brain electrochemical gradients, and can provide lasting inhibitory plasticity and neuroprotection, but its role in ECT's effects remains unknown. In this K08 proposal, I hypothesize that CSD, rather than seizure itself, drives the therapeutic effects of ECT. I will test CSD's role using the Scn1a+/- mouse model of DS, which exhibits multi-domain behavioral and neurophysiological abnormalities recapitulating human DS features. My preliminary data suggest that Scn1a+/- pathology may reverse following treatments that trigger CSD. Aim 1 tests if CSD drives ECT-induced plasticity in abnormal behavior and physiology. Wild-type and Scn1a+/- mice will receive ECT protocols designed to elicit seizure with/without CSD, CSD alone, or sham treatment. I will longitudinally monitor ECT effects on behavior (machine learning analysis of naturalistic behaviors and task assays), physiology (resting and ictal), and survival. Aim 2 uses two-photon imaging to zoom in on CSD's role in ECT effects on hyperactive neural circuits, focusing on GABAergic parvalbumin interneurons uniquely affected by Scn1a loss. Aim 3 uses single-nucleus RNA sequencing to identify cell-type-specific molecular targets of ECT plasticity, exploring if CSD normalizes abnormal GABAergic interneuron transcription. This work addresses critical gaps in our understanding of ECT's mechanism of action, and will enable future translational developments to optimize ECT and develop new mechanism-targeted brain stimulation therapies. In addition to preclinically validating CSD as a causal mechanism, this proposal will develop a novel seizure-free brain stimulation therapy that directly targets CSD. This K08 proposal will provide me with comprehensive training from Dr. Goldberg and my interdisciplinary mentorship team, in the rich scientific environment of UPenn/CHOP, focusing on advanced behavioral phenotyping, circuit-level neurophysiology, single-cell transcriptomics, and big data analysis. My training plan will help me establish my independent, R01-funded translational laboratory that defines the mechanisms of ECT and develops novel brain stimulation therapies.
