Abstract
Many studies suggest that the majority of seizure-induced cell death is associated with status epilepticus (SE); in contrast, spontaneous recurrent epileptiform discharges (SREDs) associated with epilepsy do not cause neuronal death. Extracellular factors affecting neuronal responsiveness, and compensatory changes in brain physiology, complicate assessment of cell death in vivo as the result of seizures. Our laboratory used well-characterized hippocampal neuronal culture models of SE and SREDs to investigate the direct effects of continuous and episodic epileptiform discharges on cell death in a controlled extracellular environment. The results from this study indicate that low Mg2+-induced SE, as confirmed by occurrence of high-frequency spiking, can cause neuronal death in a time-dependent manner. SE-induced cell death was found to be dependent upon extracellular calcium that enters cells primarily through the N-methyl-d-aspartate channel. In contrast, episodic seizure activity occurring for the life of the neurons in culture, as confirmed by occurrence of SREDs, was not associated with increased cell death. Further, we also observed that buildup of glutamate in the culture media, as a result of seizure activity, was not responsible for cell death. Our data confirm clinical and animal observations that SREDs do not initiate cell death. This model provides a powerful in vitro tool for carefully evaluating the effects of seizure activity on neuronal viability in the absence of various confounding factors, and may provide insights into the development of novel therapeutic agents to prevent neuronal injury during continuous seizure activity.
Published Version
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