# Mechanisms of Seizure Resistance in a Mouse Genetic Model with Altered Metabolism > **NIH NIH R37** · HARVARD MEDICAL SCHOOL · 2024 · $411,038 ## Abstract PROJECT SUMMARY / ABSTRACT Drug-resistant epilepsy is seriously debilitating and very common, affecting about one-third of the 1-2% of people who experience epilepsy during their lifetime. One of the most effective treatments for drug-resistant epilepsy is dietary therapy, in the form of a very-low-carbohydrate, ketogenic diet. Despite its effectiveness, this diet is not very widely used because of the stringency of the diet and the high commitment required of clinicians and other caregivers. It would be very valuable to understand the mechanism by which altered metabolism produces resistance to epileptic seizures, to “reverse-engineer” it, and to discover alternative pharmacologic ways of tapping into this potent and apparently unique anti-seizure mechanism. We have identified a mouse model that recapitulates the seizure resistance seen in ketogenic diet, but that involves a mutation in a single gene, Bad. The seizure resistance in this genetic model is due to alteration in brain cell metabolism, with less glucose utilization and better utilization of alternative fuels such as ketone bodies, similar to the metabolic changes on a ketogenic diet. We have also discovered a downstream mechanism that is altered both by Bad alteration and by ketogenic diet: a metabolically sensitive class of ion channels, the ATP- sensitive potassium channels (KATP channels), become more activated in response to metabolic changes. These channels are critical for seizure resistance of the Bad-altered mice, and we have also found that they are responsible for anti-seizure effects of BAD knockout in a brain slice model of seizure. Recent findings reveal that BAD knockout produces specific changes in core carbon metabolism – specifically in the pentose phosphate pathway (PPP) – and that direct manipulation of the PPP can recapitulate the cellular changes in KATP channel activity that underlie the metabolic seizure resistance in BAD knockout. We propose to test two complementary hypotheses of how altered PPP activity can signal to KATP channels, and distinguishing these hypotheses is important because they make opposite predictions for how antioxidants, alternative neuronal fuels, and oxidative signaling may alter the antiseizure effects both in BAD knockout and in dietary treatment. One hypothesis focuses on the reduced ability in BAD knockout for the neuronal PPP to produce NADPH, which is central to cellular antioxidant function; this could make native reactive oxygen signaling more effective. The second hypothesis is that it is not the reduced ability to produce the NADPH byproduct, but rather the reduced substrate flux through the PPP that alters downstream energy metabolism. We will also expand our in vivo studies, testing the ability of BAD and PPP manipulation to affect seizures in a chronic mouse model of epilepsy, Together these studies will reveal the mechanistic basis of metabolic seizure resistance, and will point toward new therapeutic avenues for drug-resist... ## Key facts - **NIH application ID:** 10896445 - **Project number:** 5R37NS102586-07 - **Recipient organization:** HARVARD MEDICAL SCHOOL - **Principal Investigator:** GARY I YELLEN - **Activity code:** R37 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $411,038 - **Award type:** 5 - **Project period:** 2018-03-01 → 2027-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10896445 ## Citation > US National Institutes of Health, RePORTER application 10896445, Mechanisms of Seizure Resistance in a Mouse Genetic Model with Altered Metabolism (5R37NS102586-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10896445. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*