LONG-DURATION SELF-SUSTAINED EPILEPTIFORM ACTIVITY IN THE HIPPOCAMPALPARAHIPPOCAMPAL SLICE - A MODEL OF STATUS EPILEPTICUS

1. Combined hippocampal-parahippocampal slices were employed to study the development of complex epileptiform discharges after Schaeffer col lateral stimulation in vitro. With repeated stimulation, slices genera ted several different types of epileptiform discharges, which were tem porally linked to the preceding stimulus, and predictable in their pro gression. The first epileptiform discharge to be elicited by stimulati on was a primary afterdischarge, which began immediately after the sti mulation train and progressed with repeated stimulation until it had p eaked in amplitude and duration by the third to fifth stimulus train. After development of the primary afterdischarge, a secondary afterdisc harge began to appear, with a 2- to 5-min latency after the third to s ixth stimulation train, and progressed in amplitude and duration with repeated stimulation, sometimes to durations >30 min. 2. After develop ment of the secondary afterdischarge, 65-70% of rostral slices trigger ed long-duration, spontaneous self-sustained activity. This activity c onsisted of repeated spontaneous 3- to 5-min duration ictallike discha rges with a short interval (<15 min between events), lasting for hours in many cases. These discharges were similar to activity seen in dept h recordings of patients with complex partial status epilepticus. This cyclic spontaneous epileptiform activity was blocked by diazepam (100 nM to 1 mu M), and potentiated by the N-methyl-D-aspartate (NMDA) ant agonist 2-amino-5-phosphonovaleric acid (APV, 50 mu M). Analysis of th e temporal progression of epileptiform activity through multiple chann el extracellular recordings demonstrated that both the interictal and ictal discharges evident during spontaneous recurrent ictallike status epilepticus (SE) originated at a site distant from the stimulation lo cus, and then propagated to area CA1. 3. Intracellular recordings from CA3 neurons during spontaneous recurrent ictallike SE activity reveal ed the cellular correlates of this activity. Recurrent ictallike disch arges were initiated at a cellular level by a large depolarization, ac companied by tonic action-potential firing. As the ictal event progres sed, the neuron continued to depolarize, and a period of depolarizatio n 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 sl ices. This type of continuous sustained activity was initiated by an i ncrease in duration of the secondary afterdischarge to 30-120 min dura tion with repeated stimulation. These sustained discharges were also i ncreased in amplitude and frequency by APV (50 mu M) and reduced or bl ocked by the benzodiazepines diazepam or clonazepam (1 mu M). Sustaine d epileptiform discharges seen in vitro were similar to one form of se izure discharges seen in patients with SE in their frequency, duration , in their progression through a similar electrographic series of stag es, and their sensitivity to benzodiazepines. 5. Intracellular recordi ngs from CA3 neurons during continuous SE-like discharges revealed lar ge bursts within this area during generation of generalized epileptifo rm activity. These bursts were coincident with extracellularly recorde d population burst activity in CA1, and so were a circuit phenomenon. 6. This physiological and pharmacological correspondence between the m ultiple types of SE-like activity seen in vitro and in patients with S E suggests that these long-duration limbic discharges seen in slices m ay 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 imp ortant in generation and control of this grave neurological condition.