Minimal latency to hippocampal epileptogenesis and clinical epilepsy after perforant pathway stimulation‐induced status epilepticus in awake rats

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Abstract
Hippocampal epileptogenesis is hypothesized to involve secondary mechanisms triggered by initial brain injury. Chemoconvulsant‐induced status epilepticus has been used to identify secondary epileptogenic mechanisms under the assumption that a seizure‐free, preepileptic “latent period” exists that is long enough to accommodate delayed mechanisms. The latent period is difficult to assess experimentally because early spontaneous seizures may be caused or influenced by residual chemoconvulsant that masks the true duration of the epileptogenic process. To avoid the use of chemoconvulsants and determine the latency to hippocampal epileptogenesis and clinical epilepsy, we developed an electrical stimulation‐based method to evoke hippocampal discharges in awake rats and produce hippocampal injury and hippocampal‐onset epilepsy reliably. Continuous video monitoring and granule cell layer recording determined whether hippocampal epileptogenesis develops immediately or long after injury. Bilateral perforant pathway stimulation for 3 hours evoked granule cell epileptiform discharges and convulsive status epilepticus with minimal lethality. Spontaneous stage 3–5 behavioral seizures reliably developed within 3 days poststimulation, and all 72 spontaneous behavioral seizures recorded in 10 animals were preceded by spontaneous granule cell epileptiform discharges. Histological analysis confirmed a reproducible pattern of limited hippocampal and extrahippocampal injury, including an extensive bilateral loss of hilar neurons throughout the hippocampal longitudinal axis. These results indicate that hippocampal epileptogenesis after convulsive status epilepticus is an immediate network defect coincident with neuron loss or other early changes. We hypothesize that the latent period is directly related and inversely proportional to the extent of neuron loss in brain regions involved in seizure initiation, spread, and clinical expression. J. Comp. Neurol. 510:561–580, 2008.