Metabolic control of neuronal activation and epilepsy

The fundamental role of metabolism in the regulation of neuronal activation is not well understood. Glycolysis is thought to support active neurons as a supplement to mitochondrial respiration in times of high metabolic demand which occurs through the astrocyte neuron lactate shuttle (ANLS). Recent evidence, however, strongly refutes this claim and argues that acute neuronal stimulation directly leads to neuronal glucose utilization through glycolysis, which becomes the primary source of ATP. Due to this lack of clarity, the role of metabolism in epilepsy formation is also unknown. In the present work, we explore the neuronal metabolic phenotype during times of high metabolic demand from chronic stimulation. We extend these findings toward understanding metabolism’s role in regulating epilepsy.

In our first aim we used a novel model of chronic activation and resected human tissue to demonstrate that chronic neuronal stimulation leads to neuronal metabolic reprogramming from aerobic respiration to glycolysis through the upregulation of neuronal LDHA. Our results challenge the prevailing ANLS hypothesis, which holds that the majority of metabolism occurs via supporting astrocytes during times of high neuronal metabolic demand. The second aim of our study was to describe the molecular pathway that regulates the transition from aerobic respiration to glycolysis during chronic neuronal stimulation. Drawing from similarities of high energy demands during hypoxia, we hypothesized that the AMPK/HIF1a hypoxia pathway plays a role in regulating neuronal metabolism during chronic stimulation. Using this model, we confirmed that neuronal metabolic reprogramming to glycolysis is mediated by the AMPK/HIF1a hypoxia pathway. For our third aim, we applied insights gained from the neuronal metabolic phenotype during times of chronic stimulation from our first two aims to more clearly elucidate the etiology of epilepsy formation. We showed that LDHA, regulated by upstream HIF1a, leads to epileptiform activity in culture and in an animal model.

Collectively, the work presented here lays the foundation of an overarching hypothesis for metabolically driven pathogenesis of epilepsy. We believe a feedforward loop exists wherein chronic seizure activity shifts neurons into glycolysis through AMPK/HIF1a mediated upregulation of LDHA, which further pushes neurons to become hyperexcitable and subsequently elicit more seizures.