Injury induced epileptogenesis: Contribution of active inhibition, disfacilitation and deafferentation to seizure induction in thalamocortical system

Abstract

Neocortical seizures are the seizures in which neocortex is the leading structure. They are characterized by spike-wave (SW) or spike-wave/polyspike-wave (SW/PSW) complexes of 1.5-3 Hz, intermingled with episodes of fast runs at ∼10-20 Hz. These seizures often develop during slow-wave sleep, transition from wake to slow-wave sleep or transition from slow-wave sleep to waking state. Intracellular studies on both anesthetized and non-anesthetized cats have shown that hyperpolarizing phase of the slow oscillation, a distinct feature of slow-wave sleep, is associated with disfacilitation, a temporal absence of synaptic activity in all cortical neurons. Periods of disfacilitation temporally increase network excitability. The hyperpolarizing components of SW-PSW complexes are mediated mainly by leak current (state similar to discfacilitation), Ca2+- and Na+-activated K+ currents. It is proposed that prolonged periods of disfacilitation up-regulate neuronal excitability that contributes to the seizure generation. Once seizure has started, fast-spiking inhibitory interneurons fire multiple action potentials during paroxysmal depolarizing shifts (EEG spike components of SW/PSW complexes). During seizure a set of cellular processes induces a shift of reversal potential of GABA toward depolarization. Intense firing of GABAergic neurons and depolarizing GABA responses largely contribute to the generation of paroxysmal EEG spikes. Inhibition does not play a role in other components of neocortical seizures. Neocortical trauma, in particular penetrating wounds, produces partial deafferentation of a subset of neurons that decreases excitability of network. Cortical neurons display occasional periods of disfacilitation in deafferented cortex during all states of vigilance. As in the case of slow-wave sleep, periods of disfacilitation up-regulate neuronal excitability. Synaptic volleys originating from preserved axons impinge hyperexcitable neurons of deafferented cortex that trigger seizures. I propose that any physiological or pathological condition that leads to repeated or prolonged periods of neuronal silence will increase neuronal hyperexcitability that favours development of seizures.