Is neuronal death required for seizure-induced epileptogenesis in the immature brain?

Abstract

Do seizures cause neuronal death? At least in the immature hippocampus, this may not be the critical question for determining the mechanisms of epileptogenesis. Neuronal injury and death have clearly been shown to occur in most epilepsy models in the mature brain, and are widely considered a prerequisite to seizure-induced epilepsy. In contrast, little neuronal death occurs after even a severe and prolonged seizure prior to the third postnatal week. However, seizures early in life, for example prolonged experimental febrile seizures, can profoundly and permanently change the hippocampal circuit in a pro-epileptogenic direction. These seizure-induced alterations of limbic excitability may require transient structural injury, but are mainly due to functional changes in expression of gene coding for specific receptors and channels, leading to altered functional properties of hippocampal neurons. Thus, in some pro-epileptogenic models in the developing brain, neither the death of neurons nor death-induced abnormalities of surviving neurons may underlie the formation of an epileptic circuit. Rather, findings in the experimental prolonged febrile seizure model suggest that persistent functional alterations of gene expression ('neuroplasticity') in diverse hippocampal neuronal populations may promote pro-epileptogenic processes induced by these seizures. These findings also suggest that during development, relatively short, intense bursts of neuronal activity may disrupt 'normal' programmed maturational processes to result in permanent, selective alterations of gene expression, with profound functional consequences. Therefore, determining the cascade of changes in the programmed expression of pertinent genes, including their temporal and cell-specific spatial profiles, may provide important information for understanding the process of transformation of an evolving, maturing hippocampal network into one which is hyperexcitable.

Brain Injury and Recovery Following Binge Ethanol: Evidence from In Vivo Magnetic Resonance Spectroscopy

“…Postmortem studies have interpreted an increase in acquired argyrophilia in rodent corticolimbic regions following 4 days of binge EtOH exposure as reflecting irreversible neuronal degeneration (7, 15). However, recent findings suggest that not all silver-stained neurons die; indeed, argyrophilia is often seen in only temporarily injured and recovering neurons (40–42). Given the rapid reversibility of the considerable ventricular enlargement observed in this study, it is proposed that brain cells (neurons, astrocytes, oligodendrocytes, microglia) and their processes shrink rather than degenerate in response to binge EtOH exposure (43, 44).…”

Lithium pilocarpine-induced status epilepticus in postnatal day 20 rats results in greater neuronal injury in ventral versus dorsal hippocampus

“…Our results suggest that the degree of neuronal injury in the ventral hippocampus, although clearly present in every animal, is in most cases too small to be detected by Nissl cell counting methods. Even if one assumes that every Fluoro-jade B neuron is lost, an assumption challenged by some researchers (Baram, 2002), in most cases it would be too small to be detected in the dorsal hippocampus with cell counting methods. If some injured Fluoro-jade B neurons recovered, the amount of neuronal loss would be even lower.…”

Ketogenic Diets: Evidence for Short- and Long-term Efficacy

“…In considering such specific effects, it should be noted that epilepsy can develop without overt evidence of neuronal injury, 37 and neuronal damage does not necessarily lead to epilepsy. 38 Hence, the terms “neuroprotection” and “anti-epileptogenesis” are not necessarily synonymous.…”