Long-duration self-sustained epileptiform activity in the hippocampal-parahippocampal slice: a model of status...

1. Combined hippocampal-parahippocampal slices were employed to study the development of complex epileptiform discharges after Schaeffer collateral stimulation in vitro. With repeated stimulation, slices generated several different types of epileptiform discharges, which were temporally linked to the preceding stimulus, and predictable in their progression. The first epileptiform discharge to be elicited by stimulation was a primary afterdischarge, which began immediately after the stimulation train and progressed with repeated stimulation until it had peaked in amplitude and duration by the third to fifth stimulus train. After development of the primary afterdischarge, a secondary afterdischarge began to appear, with a 2- to 5-min latency after the third to sixth stimulation train, and progressed in amplitude and duration with repeated stimulation, sometimes to durations > 30 min. 2. After development of the secondary afterdischarge, 65-70% of rostral slices triggered long-duration, spontaneous self-sustained activity. This activity consisted of repeated spontaneous 3- to 5-min duration ictallike discharges with a short interval (< 15 min between events), lasting for hours in many cases. These discharges were similar to activity seen in depth recordings of patients with complex partial status epilepticus. This cyclic spontaneous epileptiform activity was blocked by diazepam (100 nM to 1 microM), and potentiated by the N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovaleric acid (APV, 50 microM). Analysis of the temporal progression of epileptiform activity through multiple channel extracellular recordings demonstrated that both the interictal and ictal discharges evident during spontaneous recurrent ictal-like status epilepticus (SE) originated at a site distant from the stimulation locus, and then propagated to area CA1. 3. Intracellular recordings from CA3 neurons during spontaneous recurrent ictallike SE activity revealed the cellular correlates of this activity. Recurrent ictallike discharges were initiated at a cellular level by a large depolarization, accompanied by tonic action-potential firing. As the ictal event progressed, the neuron continued to depolarize, and a period of depolarization block ensued, which was terminated by the gradual repolarization of the neuron, with accompanying phasic burst firing. 4. A second variety of long-duration self-sustained activity was also seen in 5-10% of slices. This type of continuous sustained activity was initiated by an increase in duration of the secondary afterdischarge to 30-120 min duration with repeated stimulation. These sustained discharges were also increased in amplitude and frequency by APV (50 microM) and reduced or blocked by the benzodiazepines diazepam or clonazepam (1 microM). Sustained epileptiform discharges seen in vitro were similar to one form of seizure discharges seen in patients with SE in their frequency, duration, in their progression through a similar electrographic series of stages, and their sensitivity to benzodiazepines. 5. Intracellular recordings from CA3 neurons during continuous SE-like discharges revealed large bursts within this area during generation of generalized epileptiform activity. These bursts were coincident with extracellularly recorded population burst activity in CA1, and so were a circuit phenomenon. 6. This physiological and pharmacological correspondence between the multiple types of SE-like activity seen in vitro and in patients with SE suggests that these long-duration limbic discharges seen in slices may constitute a valuable model for study of the seizure discharges of SE. Future studies exploiting the advantages of in vitro preparations may aid in understanding physiological and pharmacological factors important in generation and control of this grave neurological condition.