Epileptogenesis in the immature brain: emerging mechanisms

Abstract

Epileptogenesis is defined as the process of developing epilepsy-a disorder characterized by recurrent seizures-following an initial insult. Seizure incidence during the human lifespan is at its highest in infancy and childhood. Animal models of epilepsy and human tissue studies suggest that epileptogenesis involves a cascade of molecular, cellular and neuronal network alterations. Within minutes to days following the initial insult, there are acute early changes in neuronal networks, which include rapid alterations to ion channel kinetics as a result of membrane depolarization, post-translational modifications to existing functional proteins, and activation of immediate early genes. Subacute changes occur over hours to weeks, and include transcriptional events, neuronal death and activation of inflammatory cascades. The chronic changes that follow over weeks to months include anatomical changes, such as neurogenesis, mossy fiber sprouting, network reorganization, and gliosis. These epileptogenic processes are developmentally regulated and might contribute to differences in epileptogenesis between adult and developing brains. Here we review the factors responsible for enhanced seizure susceptibility in the developing brain, and consider age-specific mechanisms of epileptogenesis. An understanding of these factors could yield potential therapeutic targets for the prevention of epileptogenesis and also provide biomarkers for identifying patients at risk of developing epilepsy or for monitoring disease progression.

Figure 1. Schematic depiction of maturational changes in glutamate and GABA receptor function in the developing brain

Equivalent developmental periods are displayed for rats and humans on the top and bottom x-axes, respectively. Activation of GABA receptors is depolarizing in rats early in the first postnatal week and in humans up to and including the neonatal period. Functional inhibition, however, is gradually reached over development in rats and humans. Before full maturation of GABA-mediated inhibition, the NMDA and AMPA subtypes of glutamate receptors peak between the first and second postnatal weeks in rats and in the neonatal period in humans. Kainate receptor binding is initially low and gradually rises to adult levels by the fourth postnatal week. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate; P, postnatal day.

Figure 2. Time course of epileptogenesis

An initial insult, such as traumatic brain injury and/or status epilepticus, is followed by a latent period lasting weeks to months or even years before the onset of spontaneous seizures. During this latent period, a cascade of molecular and cellular events occurs that alters the excitability of the neuronal network, ultimately resulting in spontaneous epileptiform activity. The alterations that occur during the latent period might provide a good opportunity for biomarker development and therapeutic intervention. The cascade of events that are presently suggested by experimental evidence can be classified temporally following the initial insult. Early changes, including induction of immediate early genes and post-translational modification of receptor and ion-channel related proteins, occur within seconds to minutes. Within hours to days, there can be neuronal death, inflammation, and altered transcriptional regulation of genes, such as those encoding growth factors. A later phase, lasting weeks to months, includes morphological alterations such as mossy fiber sprouting, gliosis, and neurogenesis.