A Feedforward Mechanism for Epilepsy Regulated by Lactate Dehydrogenase A
Abstract number :
1.002
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2019
Submission ID :
2420998
Source :
www.aesnet.org
Presentation date :
12/7/2019 6:00:00 PM
Published date :
Nov 25, 2019, 12:14 PM
Authors :
Alexander Ksendzovsky, Yale University; Marcelle Altshuller, Surgical Neurology Branch, NINDS, NIH; Stuart Walbridge, Surgical Neurology Branch, NINDS, NIH; Muzna Bachani, NIH; John M. Williamson, University of Virginia; Suchitra Joshi, University of Virg
Rationale: Despite the ketogenic diet's successful use since the 1920's, epilepsy as a disease of energy metabolism is a novel concept. We previously established that seizures deplete neuronal energy stores and reprogram neurons from an aerobic to glycolytic metabolic phenotype, marked by upregulation of lactate dehydrogenase A (LDHA). LDHA has recently been shown to play a role in neuronal membrane depolarization and epileptogenesis. We show here that LDHA upregulation through HIF1a leads to seizure formation. Methods: Resected tissue from 11 epileptic patients were probed for LDHA expression. To study the electrophysiological consequences of LDHA, we used a mixed rat cortical cell culture model on a microelectrode array (MEA). Furthermore, Fwe used a lentivirus vector to directly upregulate LDHA in neurons cultured on an MEA to measure neuronal bursting. Finally, we developed a novel murine model of chronic focal cortical epilepsy to establish HIF1a's role in mediating LDHA expression and seizure formation. Results: We found that LDHA increased significantly in epileptic tissue versus non-epileptic tissue. Induction of seizure activity in cultured neurons with low Mg2+resulted in increased LDHA and subsequently increased baseline bursting over ten days. Direct LDHA upregulation with an LDHA lentivirus vector resulted in increased bursting activity confirming that LDHA leads to seizure formation. Cells that were induced to upregulate LDHA via DMOG, an upstream HIF1a potentiator, showed a significant increase in baseline bursting activity. Furthermore, placement of cobalt, a HIF1astabilizer, into the frontal cortex of mice caused seizures emanating from perilesion cortex which showed increased LDHA. Conclusions: Overall, our data show that LDHA, regulated by HIF1a, can contribute to seizure development. These data suggest a novel molecular mechanism for the pathogenesis of epilepsy where seizures cause LDHA upregulation which then further drives seizures, leading to a cycle of epileptogenesis. Funding: No funding
Basic Mechanisms