Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans

Abstract

Metabolic dysfunction has been implicated in the pathogenesis of temporal lobe epilepsy (TLE), but its manifestation during neuronal activation in the ex vivo hippocampus from TLE patients has not been shown. We characterized metabolic and mitochondrial functions in acute hippocampal slices from pilocarpine-treated, chronic epileptic rats and from pharmaco-resistant TLE patients. Recordings of NAD(P)H fluorescence indicated the status of cellular energy metabolism, and simultaneous monitoring of extracellular potassium concentration ([K+]o) allowed us to control the induction of neuronal activation. In control rats, electrical stimulation elicited biphasic NAD(P)H fluorescence transients that were characterized by a brief initial 'drop' and a subsequent prolonged 'overshoot' correlating to enhanced NAD(P)+ reduction. In chronic epileptic rats, overshoots were significantly smaller in area CAI, but not in the subiculum as compared to controls. In TLE patients, who were histopathologically classified in groups with and without Ammon's horn sclerosis (AHS, non-AHS), large drops and very small overshoots of NAD(P)H transients were observed in dentate gyrus, CA3, CAI and subiculum. Nevertheless, monitoring mitochondrial membrane potential (ΔΨm) by mitochondria-specific, voltage-sensitive dye (rhodamine-123) revealed similar mitochondrial responses during neuronal activation with glutamate and protonophore application in area CAI of control and chronic-epileptic rats. Applying confocal laser scanning microscopy, these findings were confirmed in individual neurons of AHS tissue, indicating a negative ΔΨm and activation-dependent mitochondrial depolarization. Our data demonstrate severe metabolic dysfunction during neuronal activation in the hippocampus from chronic epileptic rats and humans, although mitochondria maintain negative ΔΨm. Thus, our findings provide a cellular correlate for 'hypometabolism' as described for epilepsy patients and suggest mitochondrial enzyme defects in TLE. © The Author (2005), Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.