Synaptic transmission modulates while non-synaptic processes govern the transition from pre-ictal to seizure activity in vitro

Abstract It is well established that non-synaptic mechanisms can generate electrographic seizures after blockade of synaptic function. We investigated the interaction of intact synaptic activity with non-synaptic mechanisms in the isolated CA1 region of rat hippocampal slices using the “elevated-K + ” model of epilepsy. Elevated K + ictal bursts share waveform features with other models of electrographic seizures, including non-synaptic models where chemical synaptic transmission is suppressed, such as the low-Ca 2+ model. These features include a prolonged (several seconds) negative field shift associated with neuronal depolarization and superimposed population spikes. When population spikes are disrupted for up to several seconds, intracellular recording demonstrated that the prolonged suppression of population spikes during ictal activity was due to depolarization block of neurons. Elevated-K + ictal bursts were often preceded by a build-up of “pre-ictal” epileptiform discharges that were characterized as either “slow-transition” (localized and with a gradual increase in population spike amplitude, reminiscent non-synaptic neuronal aggregate formation, presumed mediated by extracellular K+ concentrations ([K+]) o accumulation), or “fast-transition” (with a sudden increase in population spike amplitude, presumed mediated by field effects). When ictal activity had a fast-transition it was preceded by fast-transition pre-ictal activity; otherwise population spikes developed gradually at ictal event onset. Addition of bicuculline, a GABAA receptor antagonist, suppressed population spike generation during ictal activity, reduced pre-ictal activity, and increased the frequency of ictal discharges. Nipecotic acid and NNC-711, both of which block GABA re-uptake, increased population spike amplitude during ictal bursts and promoted the generation of preictal activity. By contrast, addition of ionotropic glutamate-receptor antagonists (NBQX, D-APV) had no consistent effect on ictal burst waveform or frequency and did not fully suppress pre-ictal activity. Similarly, CGP 55848, a GABA B receptor antagonist, has no significant effect on pre-ictal activity or burst frequency (although it did increase burst duration slightly). Our results are consistent with the hypothesis that non-synaptic mechanisms underpin the generation of ictal bursts in CA1 and that GABA A synaptic mechanisms can shape event development by delaying event initiation and counteracting depolarization block.