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The Journal of Neuroscience, April 27, 2005, 25(17):4260-4269; doi:10.1523/JNEUROSCI.4000-04.2005

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Neurobiology of Disease
Mitochondrial Calcium Ion and Membrane Potential Transients Follow the Pattern of Epileptiform Discharges in Hippocampal Slice Cultures

Richard Kovács,^1,2 Julianna Kardos,¹ Uwe Heinemann,² and Oliver Kann²

¹Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, 1525 Budapest, Hungary, and ²Institute for Neurophysiology, Charité-Universitätsmedizin Berlin, D-10117 Berlin, Germany

Emerging evidence suggests that mitochondrial dysfunction contributes to the pathophysiology of epilepsy. Recurrent mitochondrial Ca²⁺ ion load during seizures might act on mitochondrial membrane potential (m) and proton motive force. By using electrophysiology and confocal laser-scanning microscopy, we investigated the effects of epileptiform activity, as induced by low-Mg²⁺ ion perfusion in hippocampal slice cultures, on changes in m and in mitochondrial Ca²⁺ ion concentration ([Ca²⁺]_m).

The mitochondrial compartment was identified by monitoring m in the soma and dendrites of patched CA3 pyramidal cells using the mitochondria-specific voltage-sensitive dye rhodamine-123 (Rh-123). Interictal activity was accompanied by localized mitochondrial depolarization that was restricted to a few mitochondria in small dendrites. In contrast, robust Rh-123 release into the cytosol was observed during seizure-like events (SLEs), indicating simultaneous depolarization of mitochondria. This was critically dependent on Ca²⁺ ion uptake and extrusion, because inhibition of the mitochondrial Ca²⁺ ion uniporter by Ru360 and the mitochondrial Na⁺/Ca²⁺ ion exchanger by 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one but not the inhibitor of mitochondrial permeability transition pore, cyclosporin A, decreased the SLE-associated mitochondrial depolarization.

The Ca²⁺ ion dependence of simultaneous mitochondrial depolarization suggested enhanced Ca²⁺ ion cycling across mitochondrial membranes during epileptiform activity. Indeed, [Ca²⁺]_m fluctuated during interictal activity in single dendrites, and these fluctuations spread over the entire mitochondrial compartment during SLEs, as revealed using mitochondria-specific dyes (rhod-2 and rhod-ff) and spatial frequency-based image analysis. These findings strengthen the hypothesis that epileptic activity results in Ca²⁺ ion-dependent changes in mitochondrial function that might contribute to the neuronal injury during epilepsy.

Key words: mitochondria; epilepsy; hippocampus; calcium; patch clamp; imaging

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Received Sep 27, 2004; revised March 8, 2005; accepted March 14, 2005.

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