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

Abstract

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 GABAB 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‐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 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.

Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus

“…The proportion of brain circuits effected by activity-dependent Claccumulation will vary considerably between patients depending on the seizure type as well as the extent to which different brain areas are recruited into the seizure process. Interactions between areas may also be critical in providing pacemaker drives (Codadu et al, 2018), thereby maintaining a high rate of discharge, but breaking this loop by slightly reducing the intrinsic rate at a particular site may be all that is required. In regions where intracellular Cland EGABA are still low, benzodiazepines will enhance inhibitory restraint.…”

“…By recording GABA currents at different holding voltages gGABA could be measured before and after 30 mins exposure to 0 Mg 2+ in the same neuron. GABAB receptor blockade to isolate GABAARs was not utilised as this could interfere with the seizure-like activity evoked by 0 Mg 2+ (Swartzwelder et al, 1987;Codadu et al, 2018). Following termination of SE-like activity using reintroduction of Mg 2+ , gGABA was remeasured.…”

Divergent paths to seizure-like events

“…Brain slices were prepared in the same way (often from the same animals), from young, adult mice. We showed previously that the two models affect hippocampal and neocortical areas differently 32 (note that the entorhinal cortex appears to align with neocortical activity, rather than the hippocampal circuitry, in this regard), with the hippocampal territories being activated early in 4AP, but very late in 0 Mg 2+ . Here we focused on neocortical activity patterns, and showed that 4AP has an especially strong effect on PV-expressing interneurons (although it also alters, to a lesser extent, activity in both SST-expressing interneurons and pyramidal cells), triggering spontaneous bursting in these cells (similar results have also been reported by Williams and Hablitz 33 ).…”

Propagating Activity in Neocortex, Mediated by Gap Junctions and Modulated by Extracellular Potassium

“…Raised extracellular K 1 will also facilitate chloride loading, which is coupled via the cation-chloride cotransporter KCC2. In either case, whether GABAergic output is inhibitory or excitatory, the enhanced coupling of interneurons through their gap junctions is likely to be an important determinant of the complex pattern of propagating local field potentials during a seizure (Viventi et al, 2011;Smith et al, 2016;Codadu et al, 2019b). It is also highly pertinent that gap junction expression is commonly increased in epileptic brains (Manjarrez-Marmolejo and Franco-Pérez, 2016).…”