Investigating epileptiform activity associated with slow wave sleep

Abstract

The characteristic EEG trait of patients with nocturnal idiopathic epilepsies during childhood is the spike and wave discharge. Cognitive dysfunction is prevalent among these patients and is thought to be linked to disturbances in memory consolidation processes that normally occur during slow wave sleep. Several genetic mutations of nicotinic receptor subunits have been linked to these disorders. However, there is little known about the underlying mechanisms or the spatiotemporal characteristics of this epileptiform activity within the neocortex. This thesis presents a rat in vitro model of the epileptiform activity synonymous with nocturnal childhood epilepsies, that allows for pharmacological manipulation of receptor subunits linked to these disorders. The application of DTC [10 M], a non-selective, competitive nicotinic acetylcholine receptor antagonist, to an in vitro model of the cortical delta rhythm induced two individual forms of paroxysm events - wave discharges and the conventional spike and wave discharges. Pharmacological manipulation of this model suggest that the epileptiform activity is mediated by excitatory currents which is consistent with the use of glutamate antagonists as anticonvulsants. A blanket blockade of inhibition by a GABAA antagonist resulted in severe discharges, hence hugely increasing excitatory response. Only partial disinhibition is suggested to be required to generate epileptiform activity as nicotinic acetylcholine receptors and 5-HT3 receptors are located on dendrite targeting interneurons. Mapping of unit activity revealed the di erence between the two paroxysm events was recruitment of super cial layers with simultaneous paroxysm events in delta frequency-generating Layer V pyramidal cells. It is proposed that the hyperexcitability responsible for the generation of the spike component of a spike and wave discharge is mediated by the lack of excitatory tone in 5-HT3 and nicotinic acetylecholine receptor expressing inhibitory interneuron subtypes. The disinhibition, spike generation and disruption of interplay between deep and super cial layers of the neocortex is thought to be associated with synaptic plastic changes.