Brain Advance Access originally published online on June 15, 2005
Brain 2005 128(10):2396-2407; doi:10.1093/brain/awh568
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Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans
1 Institute for Neurophysiology and 2 Department of Neurosurgery, Charité—Universitätsmedizin Berlin, Germany and 3 Department of Neurochemistry, Institute of Biomolecular Chemistry, Budapest, Hungary
Correspondence to: Dr. med. Oliver Kann, Institut für Neurophysiologie, Charité—Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany E-mail: oliver.kann{at}charite.de
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 CA1, 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, CA1 and subiculum. Nevertheless, monitoring mitochondrial membrane potential (
m) by mitochondria-specific, voltage-sensitive dye (rhodamine-123) revealed similar mitochondrial responses during neuronal activation with glutamate and protonophore application in area CA1 of control and chronic-epileptic rats. Applying confocal laser scanning microscopy, these findings were confirmed in individual neurons of AHS tissue, indicating a negative m 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 m. Thus, our findings provide a cellular correlate for ‘hypometabolism’ as described for epilepsy patients and suggest mitochondrial enzyme defects in TLE.
Key Words: hypometabolism; mitochondria; NADPH; potassium [K]; temporal lobe epilepsy
Abbreviations:
m = mitochondrial membrane potential; ACSF = artificial cerebrospinal fluid; AHS = Ammon's horn sclerosis; CCCP = cyanide m-chlorophenyl hydrazone; [K+]o = extracellular potassium concentration; TLE = temporal lobe epilepsy
Received April 11, 2005. Revised May 15, 2005. Accepted May 19, 2005.
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