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

Key Points: Local neocortical and hippocampal territories show different and sterotypical patterns of acutely evolving, epileptiform activity. Neocortical and entorhinal networks show tonic-clonic-like events, but the main hippocampal territories do not, unless it is relayed from the other areas. Transitions in the pattern of locally recorded epileptiform activity can be indicative of a shift in the source of pathological activity, and may spread through both synaptic and non-synaptic means. Hippocampal epileptiform activity is promoted by 4-aminopyridine and inhibited by GABA receptor agonists, and appears far more sensitive to these drugs than neocortical activity. These signature features of local epileptiform activity can provide useful insight into the primary source of ictal activity, aiding both experimental and clinical investigation.

Abstract: Understanding the nature of epileptic state transitions remains a major goal for epilepsy research. Simple in vitro models offer unique experimental opportunities that 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 in their susceptibility to drug manipulation. In the zero-Mg 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 localized, 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.