Multiple pilocarpine-induced status epilepticus in developing rats: A long-term behavioral and electrophysiological study

Purpose: Animal models are useful for the study of status epilepticus (SE)- induced epileptogenesis and neurological sequelae, especially during early brain development. Here. we show several permanent abnormalities in animals subjected to multiple SE during early development. Methods: Wistar pup rats (7 to 9 days old) were subjected to three consecut ive episodes of SE induced by systemic pilocarpine injections. To study the long-lasting consequences of early-induced SE, chronic electroencephalogra phic recordings were made from the hippocampus and cortex and several behav ioral tests (inhibitory step-down avoidance, rota-rod, open field, elevated plus-maze, and Skinner box) were performed at postnatal days 30 to 90. We also investigated in vitro electrophysiological responses of the CA1 area u sing extracellular recordings in hippocampal slices. A histological analysi s was done using cresyl violet staining 24 hours and several months after S E induction. Apoptotic cell death was evaluated by terminal deoxynucleotidy l transferase dUTP nick-end labeling (TUNEL staining) 24 hours after the la st SE episode. Results: Electloencephalographic recordings from 30- to 90-day-old rats tha t had been subjected to multiple SE episodes in early life showed marked ch anges compared with those from nontreated controls. These included frequent episodes of continuous complex spiking activity and high-voltage ictal dis charges, with a small percentage of these rats presenting spontaneous behav ioral seizures. These animals also presented evidence of severe cognitive d eficit in adulthood. In vitro, a persistent hyperexcitability of the CAI ar ea was detected in experimental animals. Histological analysis of the brain s did not reveal any major long-term pathological changes. Nevertheless, an increased number of TUNEL-positive nuclei were present in some animals in both the hippocampus and the thalamus. Conclusions: These data show persistent abnormalities in animals subjected to multiple SE episodes during early postnatal development. SE may result i n important plastic changes in critical periods of brain maturation leading to long-lasting epileptogenesis, as manifested by electrogaphic epileptifo rm discharges, behavioral deficits, and in vitro hyperexcitability of hippo campal networks.