Region-specific differences and areal interactions underlying transitions in epileptiform activity

Abstract

Understanding the nature of epileptic state transitions remains a major goal for epilepsy research. Simple in vitro models offer unique experimental opportunities, which we exploit to show that such transitions can arise from shifts in the ictal source of the activity. These transitions reflect the fact that cortical territories differ both in the type of epileptiform activity they can sustain, and their susceptibility to drug manipulation. In the zero Mg2+ model, the earliest epileptiform activity is restricted to neocortical and entorhinal networks. Hippocampal bursting only starts much later, and triggers a marked transition in neo-/entorhinal cortical activity. Thereafter, the hippocampal activity acts as a pacemaker, entraining the other territories to their discharge pattern. This entrainment persists following transection of the major axonal pathways between hippocampus and cortex, indicating that it can be mediated through a non-synaptic route. Neuronal discharges are associated with large rises in extracellular [K+], but we show that these are very localised, and therefore are not the means of entraining distant cortical areas. We conclude instead that the entrainment occurs through weak field effects distant from the pacemaker, but which are highly effective at recruiting other brain territories that are already hyperexcitable. The hippocampal epileptiform activity appears unusually susceptible to drugs that impact on K+ conductances. These findings demonstrate that the local circuitry gives rise to stereotypical epileptic activity patterns, but these are also influenced by both synaptic and non-synaptic long-range effects. Our results have important implications for our understanding of epileptic propagation, and anti-epileptic drug action.\n\nKey pointsO_LILocal neocortical and hippocampal territories show different and sterotypical patterns of acutely evolving, epileptiform activity.\nC_LIO_LINeocortical and entorhinal networks show tonic-clonic-like events, but the main hippocampal territories do not, unless it is relayed from the other areas.\nC_LIO_LITransitions in the pattern of locally recorded epileptiform activity can be indicative of a shift in the source of pathological activity, and which may spread through both synaptic and non-synaptic means.\nC_LIO_LIHippocampal epileptiform activity is promoted by 4-aminopyridine and inhibited by GABAB agonists, and appears far more sensitive to these drugs than neocortical activity.\nC_LIO_LIThese signature features of local epileptiform activity can provide useful insight into the primary source of ictal activity, aiding both experimental and clinical investigation.\nC_LI