When and how do seizures kill neurons, and is cell death relevant to epileptogenesis?

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.

Fig. 9.1

Schematic diagrams showing hypothetical relationships of neuronal populations after a brain insult that activates cellular mechanisms of neuronal death. In the four panels of the figure, two or three populations of neurons are depicted in a schematic manner. Dead neurons (filled black triangles) are shown within a network of live and completely-normal neurons (filled red triangles). Among these two populations of cells is another group of neurons, which form the core of this hypothesis; these neurons have undergone only the initial steps of a neuronal-death and/or are under the molecular influence of the neuronal death process (black triangular outline with red stiples inside). (a) Focal neuronal loss. A small cluster of dead neurons is shown to be clumped together within a network of normal neurons, as would be expected to occur during an infarct. Between these two completely different neuronal populations is the group of neurons that are hypothetically epileptogenic, because they have undergone the first part of a neuronal-death process and/or are under the molecular influence of the neuronal death process. (b) Diffuse neuronal loss. Using the same code to define the members of the neuronal population, this diagram illustrates scattered neuronal loss, as would be expected to occur after status epilepticus (vs an infarct in (a)). (c) Occurrence of neuronal death without generation of neurons altered or influenced by death-process mechanisms, which theoretically represents the occurrence of frank brain damage without subsequent epilepsy. (d) Absence of neuronal death after a brain insult, but with the presence of death-pathway neurons. In this case, the death-pathway neurons are hypothesized to become epileptogenic, and they generate spontaneous recurrent seizures without the prior occurrence of overt neuronal death