Search

The subtle mechanisms of post-traumatic epileptogenesis remain unknown, although the incidence of chronic epilepsy after penetrating cortical wounds is high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immuno-histochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantification of the labeled neurons was performed in control animals and at 2, 4, and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals, the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, potentially explaining the increased propensity to seizures in chronic undercut cortex.

Some forms of electrographic seizures are generated at the level of the cortical network. Neocortical kindling exhibits a resistance to produce generalized convulsive seizures, and therefore, it was rather difficult to use it to study the cortical epileptogenesis. Here, using supra-threshold cortical kindling, we report electrophysiological patterns of field-potential synchronization and intracellular activities in chronically implanted non-anesthetized cats, during different states of vigilance, and during acute seizures elicited by prolonged (20-60 s) electrical stimulation. Acute seizures were easily elicited during transition from slow-wave sleep (SWS) to waking state. The seizures were mainly clonic accompanied with tonic components followed by prolonged postictal depression. Delayed rhythmic outlasting activities (OA) at approximately 1.5 Hz, first time reported here, followed the postictal depression, and lasted up to 2 h. These activities were clear during waking state, slightly reduced during SWS and completely absent during rapid-eye movement sleep. They started focally and following daily stimulations generalized over the entire cortical surface. Extra- and intracellular neuronal recordings during OA displayed spike-doublets, built on the summation of successive excitatory postsynaptic potentials and fast-prepotentials, entailing an increased dendritic excitation. Our results suggest that such rhythmic long-lasting oscillatory activity outlasting seizures are the key factor of epileptogenesis, leading to epilepsy.

Kindling is an essential operating paradigm of the nervous system extensively used both as a model of epileptogenesis and neuroplasticity. In a parallel study conducted on chronically implanted non-anesthetized kindled cats, we report the occurrence of long-lasting slow oscillatory patterns (1.5-2 Hz) called outlasting activities (OA) following the acute seizures (AS) induced by cortical stimulation. Here, we asked if OA observed in the neocortex of kindled animals are generated exclusively by the cortical networks or if they also rely on the burst firing of thalamic neurons. We analyzed the electrophysiological patterns of synchronization of cortical EEG (areas 4, 5, 7, 21, 17, 18, 22) and thalamic field (EThG) (ventral posterior lateral nucleus-VPL), and the influence of modulatory systems originating in the pedunculo-pontine tegmentum (PPT) and locus coeruleus (LC) on the discharge pattern of thalamic neurons during OA. Synchrony analysis of field recordings showed that during AS cortical paroxysmal activities preceded thalamic ones, while during OA this sequential order was reversed. During OA thalamic neurons regularly discharged bursts with the frequency of OA. Electrical stimulation of either PPT or LC during OA decreased both the probability of bursts in thalamocortical neurons and the amplitude of OA. Yet, neither of them was able to block completely the expression of OA. Following PPT/LC stimulation the burst firing of thalamocortical neurons was replaced by tonic firing. We conclude that the thalamus is involved in the mechanism of generation of OA but that it does not play an exclusive role.

To study the possible mechanism(s) underlying unresponsiveness following neocortical seizures, we recorded excitatory postsynaptic potentials (EPSPs) of cortical neurons evoked by ipsilateral cortical stimulation before and after spontaneous or elicited seizures. Regular-spiking neurons (n = 32) were intracellularly recorded in association area five of cats under ketamine-xylazine or barbiturate anesthesia. Compared with control responses, cortically evoked EPSPs were characterized by decreased amplitude after electrographic seizures. Synaptic responses and intrinsic properties were measured by applying extracellular electrical stimuli followed by intracellular hyperpolarizing current pulses. The input resistance decreased during seizures but quickly recovered to control level after the paroxysms, whereas the amplitude of evoked EPSPs remained lower following seizures, generally for 2-12 min, suggesting that the decreased EPSPs were not due to an alteration of intrinsic response. Data demonstrate a long-lasting decreased synaptic responsiveness following generalized spike-wave seizures slowly recovering in time.