Cellular Mechanisms of Epilepsy: A Status Report

Abstract

The cellular phenomena underlying focal epilepsy are currently understood in the context of contemporary concepts of cellular and synaptic function. Interictal discharges appear to be due to a combination of synaptic events and intrinsic currents, the exact proportion of which in any given neuron may vary according to the anatomic and functional substrate involved in the epileptic discharge and the epileptogenic agent used in a given model. The transition to seizure appears to be due to simultaneous increments in excitatory influences and decrements in inhibitory processes--both related to frequency-dependent neuronal events. A variety of specific hypotheses have been proposed to account for the increased excitability that occurs during epileptiform activity. Although each of the proposed mechanisms is likely to contribute significantly to the epileptic process, no single hypothesis provides an exclusive unifying framework within which all kinds of focal epilepsy can be understood. The spread of epileptic activity throughout the brain, the development of primary generalized epilepsy, the existence of "gating" mechanisms in specific anatomic locations, and the extrapolation of hypotheses derived from simple models of focal epilepsy to explain more complex forms of human epilepsy, all are not yet fully understood.

Excitatory synaptic potentials in kainic acid-denervated rat CA1 pyramidal neurons

“…The present data indicate that the sensitivity of the graded bursts to NMDA antagonists may also be another similarity (Avoli and Olivier, 1987). These findings imply that both abnormalities within single neurons (such as changes in the expression of membrane channels) as well as local circuit alterations may contribute to the hyperexcitability of cells, consistent with previous hypotheses concerning mechanisms underlying epileptiform abnormalities (Schwartzkroin and Wyler, 1980;Dichter and Ayala, 1987).…”

“…The KA lesion has been suggested to exhibit many of the characteristics of the human temporal lobe epileptic lesion, including neuron damage and loss, relative preservation of inhibitory neurons without demonstrable postsynaptic inhibition, and the presence of graded bursts (Nadler et al, 1980a,b;Lothman and Collins, 1981;Cavalheiro et al, 1982;Schwartzkroin and Knowles, 1984;Dichter and Ayala, 1987;Franck et al, 1988;Wheal, 1989). The present data indicate that the sensitivity of the graded bursts to NMDA antagonists may also be another similarity (Avoli and Olivier, 1987).…”

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

“…Abnormal neuronal excitability plays a fundamental role in the pathophysiology of epilepsy [32,33] . Depolarization block is proposed to be associated with the initiation and spread of focal epileptic seizures that generates a paroxysmal depolarizing effect in the involved neurons, which may cause the inactivation of Na + channels [31][32][33]52] .…”

“…Depolarization block is proposed to be associated with the initiation and spread of focal epileptic seizures that generates a paroxysmal depolarizing effect in the involved neurons, which may cause the inactivation of Na + channels [31][32][33]52] . In our study, the effects of SKF83959 on Na + channel density and on the Na + channel inactivation curve facilitated depolarization block in hippocampal pyramidal neurons.…”

“…Depolarization block is regarded to have pathological relevance for some brain disorders, including epilepsy and schizophrenia [32][33][34] . Among all the mechanisms known to cause depolarization block, the inactivation of voltage-dependent Na + channels is believed to play a key role [31,35,36] .…”