“Epileptic Neurons” in Temporal Lobe Epilepsy

Epilepsy is a devastating chronic neurological disorder that affects about 0.8% of the population worldwide. The clinical hallmark of epilepsy is recurrent seizures, which consist of synchronised discharges of large groups of neurons. Several lines of evidence suggest that the hippocampal formation is critically involved in TLE. Firstly, recordings from intracerebrally implanted electrodes demonstrate that the first electrographic abnormalities in temporal lobe seizures often appear within this structure (18). Secondly, surgical removal of the amygdala and hippocampal formation considerably diminishes or abolishes seizures in most TLE patients (54). Thirdly, in a large group of TLE patients, the hippocampal formation shows a characteristic and stereotypical pattern of damage, known as Ammon’s horn sclerosis, consisting of segmental neuron loss in the CA1, CA3, and CA4 subfields of the Ammon’s horn, synaptic reorganization of surviving neuronal populations and severe astrogliosis (6, 9, 36). For all these reasons, research on the mechanisms leading to increased seizure suceptibility in TLE has focused on functional and structural alterations in the hippocampus proper and its most important input and output regions, ie, the entorhinal cortex and the amygdala. Because an epileptic seizure is the manifestation of a sustained and highly synchronized discharge of a large group of neurons, a fundamental issue in TLE research is the identification of the functional changes that are responsible for abnormal neuronal recruitment and synchronization. Hitherto, most studies in experimental and clinical TLE have focused on the analysis of epilepsy-related changes in synaptic connections between neurons. A striking structural change found in hippocampi of both epileptic animals and humans is sprouting of excitatory axons and formation of new synaptic contacts on surviving neurons (5, 28, 34). A number of in vitro studies have provided preliminary evidence that such abnormal recurrent sprouting may contribute to the hyperexcitability seen in TLE (41, 51). Yet, others maintain that sprouting is not a crucial factor in epileptogenesis (30, 31). In addition to these structural changes, alterations in the density and subunit composition of neurotransmitter receptors have been reported, such as upregulation of synaptic N-methyl-D-aspartate (NMDA) receptor function (16, 27, 32, 38, 47) or changes in -amino-butyric acidA (GABAA) receptor-mediated inhibition (8, 11, 12, 14, 19, 34). These changes also are candidate mechanisms for the hippocampal hyperexcitability seen in TLE.