Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 7, Pages 1796-1806Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.099176
Keywords
Cell death; Seizure; Status epilepticus; Mitochondria; ATP; Neurons
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Funding
- Deutsche Forschungsgemeinschaft [KO-3878/1-1]
- Medical Research Council [MC_G1000735] Funding Source: researchfish
- MRC [MC_G1000735] Funding Source: UKRI
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The mechanisms underlying neuronal death following excessive activity such as occurs during prolonged seizures are unclear, but mitochondrial dysfunction has been hypothesised to play a role. Here, we tested this with fluorescence imaging techniques in rat glio-neuronal neocortical co-cultures using low Mg2+ levels to induce seizure-like activity. Glutamate activation of NMDA receptors resulted in Ca2+ oscillations in neurons and a sustained depolarisation of the mitochondrial membrane potential, which was cyclosporine A sensitive, indicating mitochondrial permeability and transition pore opening. It was also dependent on glutamate release and NMDA receptor activation, because depolarisation was not observed after depleting vesicular glutamate with vacuolar-type H+-ATPase concanamycin A or blocking NMDA receptors with APV. Neuronal ATP levels in soma and dendrites decreased significantly during prolonged seizures and correlated with the frequency of the oscillatory Ca2+ signal, indicative of activity-dependent ATP consumption. Blocking mitochondrial complex I, complex V or uncoupling mitochondrial oxidative phosphorylation under low-Mg2+ conditions accelerated activity-dependent neuronal ATP consumption. Neuronal death increased after two and 24 hours of low Mg2+ levels compared with control treatment, and was reduced by supplementation with the mitochondrial complex I substrate pyruvate. These findings demonstrate a crucial role for mitochondrial dysfunction in seizure-activity-induced neuronal death, and that strategies aimed at redressing this are neuroprotective.
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