Abstract
The effect of seizures on neuronal death and the role of seizure-induced neuronal death in acquired epileptogenesis have been debated for decades. Isolated brief seizures probably do not kill neurons; however, severe and repetitive seizures (i.e., status epilepticus) certainly do. Because status epilepticus both kills neurons and also leads to chronic epilepsy, neuronal death has been proposed to be an integral part of acquired epileptogenesis. Several studies, particularly in the immature brain, have suggested that neuronal death is not necessary for acquired epileptogenesis; however, the lack of neuronal death is difficult if not impossible to prove, and more recent studies have challenged this concept. Novel mechanisms of cell death, beyond the traditional concepts of necrosis and apoptosis, include autophagy, phagoptosis, necroptosis, and pyroptosis. The traditional proposal for why neuronal death may be necessary for epileptogenesis is based on the recapitulation of development hypothesis, where a loss of synaptic input from the dying neurons is considered a critical signal to induce axonal sprouting and synaptic-circuit reorganization. We propose a second hypothesis – the neuronal death pathway hypothesis, which states that the biochemical pathways causing programmed neurodegeneration, rather than neuronal death per se, are responsible for or contribute to epileptogenesis. The reprogramming of neuronal death pathways – if true – is proposed to derive from necroptosis or pyroptosis. The proposed new hypothesis may inform on why neuronal death seems closely linked to epileptogenesis, but may not always be.
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Acknowledgments
Ray Dingledine first met Phil Schwartzkroin in 1975 just after Phil had returned to Stanford from his postdoctoral stint with Per Andersen in Oslo, little realizing that he would follow in Phil’s footsteps by joining Per’s lab just 2 years later. Ray was in the act of returning some equipment that he had “borrowed” from David Prince’s lab to complete his graduate work, recognizing that it would never be missed in the vast warehouse of the Prince lab. Phil was then, as he is now, a very gracious yet intense scientist, and Ray values his friendship.
Ed Dudek also met Phil in about 1975; we have never worked together, but we have had numerous critical if not intense discussions on a variety of topics. Ed deeply appreciates and respects his thoughtful and constructive criticisms and his kind encouragement; Phil’s traits and his actions have made all of us better scientists and professional colleagues.
Other Acknowledgements
This work is supported by National Institutes of Health awards NS076775, NS074169, and P20 NS080185 (RD) and NS058158 (RD), and NS079135, NS079274, and NS086364 (FED). We thank Jonas Neher (Tuebingen, Germany) and Jeff Ekstrand (Salt Lake City, Utah) for helpful comments as well as Vicki Skelton (Salt Lake City, Utah) for figure preparation and assistance with the manuscript.
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Dingledine, R., Varvel, N.H., Dudek, F.E. (2014). When and How Do Seizures Kill Neurons, and Is Cell Death Relevant to Epileptogenesis?. In: Scharfman, H., Buckmaster, P. (eds) Issues in Clinical Epileptology: A View from the Bench. Advances in Experimental Medicine and Biology, vol 813. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8914-1_9
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