Abstracts

Rationale: Anaerobic respiration, marked by lactate dehydrogenase alpha (LDHA), has recently been suggested to contribute to epileptogenesis. However, the metabolic state of excited neurons and its contribution to epileptogenesis is unknown. In this study, we demonstrate a switch from aerobic to anaerobic respiration in chronically activated neurons in human and murine models of epilepsy. Our data suggest that neuronal membrane hyperexcitability induces LDHA upregulation and thus places neurons in an anaerobic state.  Methods: Based on its involvement in seizure activity as determined by intracranial monitoring, we analyzed resected human tissue for markers of anaerobic respiration. Similarly, we used rat pilocarpine and mouse pentylenetetrazole (PTZ) models to probe for these markers and upstream proteins.  Results: There was a statistically significant upregulation of neuronal LDHA protein and mRNA in resected epileptic tissue when compared to electrographically silent internal normal controls. Pilocarpine rats and PTZ mice showed a similar upregulation in LDHA when compared to control animals, which corresponded to chronicity of epilepsy and total number of seizures.  Conclusions: Our data demonstrate that chronic neuronal stimulation drives a switch from aerobic to anaerobic respiration, as marked by LDHA. To our knowledge this is the first study to suggest cellular metabolic consequences from neuronal over-activation and offers new avenues for exploration into cellular mechanisms of epilepsy.  Funding: Intramural NIH/NINDS