Age-dependent epileptogenicity: Mechanisms of seizure generalization, hippocampal neuronal damage, and reactive hyperinhibition in the dentate gyrus

Abstract

In adults, seizures can produce persistent alterations in the hippocampus, including cell death, sprouting of axonal collaterals and aberrant synaptogenesis, and alterations in synaptic transmission. Most seizure-induced alterations promote hyperexcitability and further seizure activity, leading to the theory that 'idiopathic' epilepsies in adults arise from persistent alterations induced by seizures early in life, when seizures are most common. Using the kindling model of temporal lobe epilepsy I found that immature, 16 day old, rats develop severe seizures much more rapidly than adults and that while concurrent kindling of two sites retards kindling in adults, it fosters kindling in immature rats. Immature seizure suppression mechanisms may underlie these age-dependent differences, and may explain the heightened seizure susceptibility and high incidence of multifocal seizures in neonates. The heightened seizure susceptibility, however, is countered by a reduced susceptibility to seizure-induced neuronal damage or alterations. In contrast to adults, immature rats failed to exhibit cell loss, synaptic rearrangement, or altered synaptic transmission following seizures suggesting that neonatal seizures may not produce persistent alterations which promote seizure activity later in life.;Seizure-induced enhanced dentate inhibition in adults is concurrent with, and may compensate for, seizure-induced hyperexcitability throughout the hippocampus. Using brain slice electrophysiology, I demonstrated that both GABA{dollar}\sb{lcub}\rm A{rcub}{dollar} and GABA{dollar}\sb{lcub}\rm B{rcub}{dollar} postsynaptic receptor responses in granule cells were enhanced following kainic acid seizures. The GABA{dollar}\sb{lcub}\rm B{rcub}{dollar} receptor antagonist CGP35348 enhanced both receptor responses in control slices, but failed to further enhance inhibition following seizures. I concluded that CGP35348 blocks a GABA{dollar}\sb{lcub}\rm B{rcub}{dollar} receptor normally involved in suppressing GABA release, which is downregulated after seizures. This hypothesis was supported by my findings that paired-pulse suppression of recurrent IPSPs was reduced after seizures, and that CGP35348 mimicked this reduction in control slices. However, paired monosynaptic IPSPs recorded intracellularly showed no seizure-induced difference in disinhibition, suggesting that presynaptic GABA{dollar}\sb{lcub}\rm B{rcub}{dollar} autoreceptors on inhibitory terminals were not the altered receptor population. Therefore, seizure-induced enhancements in dentate inhibition are caused, in part, by a decrease in GABA{dollar}\sb{lcub}\rm B{rcub}{dollar} receptor function in the polysynaptic recurrent inhibitory circuit, leading to more GABA release during repetitive stimulation.