# Energy and Neural Circuit Excitability

> **NIH NIH R56** · UNIVERSITY OF VIRGINIA · 2021 · $419,085

## Abstract

Project Summary
Glucose is the primary fuel used by the brain. While alternative energy substrates can transiently sustain the
brain’s needs during hypoglycemic episodes, glucose-sensing neurons within the brain nonetheless respond to
diminishing energy supplies by altering their electrical behavior. This cellular response often has significant
ramifications for the electrical activity patterns produced by glucose sensitive neural networks. Recent studies
indicate that neural circuits in the thalamus, a subcortical brain structure, are particularly vulnerable to low levels
of glucose in the blood. In this project, we aim to identify the mechanisms responsible for this heightened
glucosensitivity, and to determine how these mechanisms promote hypoglycemia-associated epileptic seizures.
Our multifaceted approach utilizes biosensor imaging and electrophysiological techniques, in both whole animals
and in vitro preparations, to test the general hypothesis that glucose metabolism directly modulates neural
circuits in the thalamus to exacerbate seizures. Using our preliminary data as a launching point, we will begin by
carrying out experiments designed to disrupt glucose metabolism while measuring seizures. Collectively, these
experiments will establish the thalamus, a critical seizure-generating node in the brain, as a glucosensitive
structure.
In conjunction with our glucose and seizure measurements, we will utilize electrophysiological and imaging
techniques in acute brain slice preparations to directly measure the sensitivity of thalamic neurons to glucose
metabolism. These experiments will be performed both at the cellular and circuit level. The former is achieved
by conventional patch clamp recordings, while the latter is achieved in well-established slice models of thalamic
seizures; our lab has extensive experience with both techniques. By performing these experiments, we aim to
pinpoint mechanisms within the thalamic circuit that are particularly vulnerable to hypoglycemic conditions.
Our Specific Aims include:
  Aim 1 Hypoglycemia-activated AMPK incites spike-wave seizures by amplifying GABAB receptor
activity.
  Aim 2 Metformin-induced lactic acidosis triggers seizures.
When complete, we expect that the results of our project will provide new and significant insights into
fundamental cellular- and circuit-level mechanisms that drive generalized seizures, and therefore pave new
avenues for generalized epilepsy treatments.

## Key facts

- **NIH application ID:** 10416150
- **Project number:** 2R56NS099586-05A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Mark Beenhakker
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,085
- **Award type:** 2
- **Project period:** 2016-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416150

## Citation

> US National Institutes of Health, RePORTER application 10416150, Energy and Neural Circuit Excitability (2R56NS099586-05A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10416150. Licensed CC0.

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