Abstracts

RATIONALE: Mitochondria play an important role in modulating neuronal excitability in normal function as well as in disease. Applying biochemical micromethods we have investigated mitochondrial oxidative phosphorylation in hippocampal subfields and the parahippocampal gyrus of pilocarpine-treated chronic epileptic rats. METHODS: We determined the oxygen consumption of 400 m hippocampal and parahippocampal microslices of pilocarpine-treated rats having spontaneous seizures applying high resolution respirometry. Additionally, we measured the activities of NADH:CoQ oxidoreductase (complex I of respiratory chain), cytochrome c oxidase (complex IV of respiratory chain) and citrate synthase and applied rhodamine 123 imaging of the mitochondrial membrane potential. RESULTS: In comparison to controls we observed an approximately two-fold reduction in the citrate synthase normalized activities of NADH:CoQ1 reductase (complex I) in the CA1 and CA3 hippocampal subfields while this activity was normal in the dentate gyrus and the parahippocampal gyrus. This enzyme activity change in both pyramidal subfields of pilocarpine-treated rats was accompanied by an approximately two-fold increase in flux control of this enzyme for mitochondrial respiration as determined by amytal titrations of oxygen consumption. On the other hand, the complex IV activities remained normal. Furthermore, we could demonstrate that the complex I deficiency was accompanied by a decrease in mitochondrial membrane potential as evidenced in rhodamine 123 stained hippocampal microslices. These findings clearly indicate that this enzyme deficiency in the CA1 and CA3 subfields severely affects neuronal energy metabolism. Most probably in response to the mitochondrial defect, the amount of somatic mitochondria increased in the CA1 and CA3 pyramidal neurons as observed by succinate dehydrogenase histochemistry. CONCLUSIONS: The observed changes of mitochondrial energy metabolism in the pilocarpine model of chronic epilepsy are proposed to affect both neuronal excitability and cell survival in vulnerable regions of the epileptic hippocampus.