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.