# Mechanisms of seizure resistance in a mouse genetic model with altered metabolism

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $384,596

## 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.
We have also recently learned that KATP channel activation depends on the expression of the BAD protein in
individual neurons, which means that the effects of BAD can be genetically targeted to individual cell types or
to specific brain regions.
This ability to target the genetic manipulation of the BAD protein – which cannot be done for a global
manipulation like diet – creates the opportunity to learn the cellular sites of action where BAD modification
is required to produce seizure resistance. We now have a conditional knockout allele of the Bad gene
(Bad flox/flox) that can be used in combination with various “driver lines” that express Cre recombinase in specific
cells. We will determine whether BAD knockout is effective in slice seizure models or against seizures in mice,
when the knockout is restricted to certain targets, for instance, to neurons in specific brain regions like the
dentate gyrus that are hypothesized to function as “seizure gates”. We will also test a pharmacological
approach to producing the anti-seizure effects of BAD, by asking whether a specific class of BAD-mimetic
compounds is capable of reversing or mimicking the effect of BAD knockout on seizure-like events in slices.
These studies will advance our mechanistic understanding of metabolic seizure resistance and more generally
of endogenous “seizure gates”, and will exp...

## Key facts

- **NIH application ID:** 9828120
- **Project number:** 5R01NS102586-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** GARY I YELLEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,596
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828120

## Citation

> US National Institutes of Health, RePORTER application 9828120, Mechanisms of seizure resistance in a mouse genetic model with altered metabolism (5R01NS102586-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828120. Licensed CC0.

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