Abstracts

Rationale: Kindling is implicated in adverse long-term consequences of epilepsy and has been proposed as an activity-dependent process that may contribute to delayed emergence of post-traumatic epilepsy (PTE) after traumatic brain injury (TBI). This study aimed to determine if unique strains of kindling-susceptible and kindling-resistant rats were differentially susceptible to development of seizures after TBI, and to define phenotypic differences between these strains pertinent to epileptogenesis. Methods: Sprague Dawley (SD) rats with "fast" and "slow" rates of perforant path kindling defined as < 10 ADs vs. >20 ADs to the first secondary generalized tonic-clonic (Class V) seizure were bred for 13 generations to produce strains of "fast" perforant path kindling-susceptible (PPKS) and "slow" perforant path kindling-resistant (PPKR) rats. TBI was induced under isoflurane anesthesia by controlled cortical impact (CCI) over temporo-parietal cortex in PPKS rats (n=9), PPKR rats (n=12). Uninjured or "sham" injured controls without CCI served as controls (SD, n=16; PPKS, n=12; PPKR, n=14). Stainless steel screw epidural electrodes were placed over each hemisphere for video-EEG recording. Additional groups of PPKS, PPKR, and SD rats were also examined for differential susceptibility to seizures evoked by pentylenetetrzol (PTZ) 50 mg/kg IP. Results: Video-EEG monitoring performed for a total of ~30 hrs in each rat for a period of ~ 4 mo revealed subtle recurring spontaneous electrographic and behavioral seizures consisting of trains of spike discharges increasing in frequency and amplitude with durations varying from 1-2 sec to as long as ~15 sec, accompanied by behavioral arrest or "freezing" resembling Class I limbic seizures which terminated with cessation of the spike discharge. These subtle seizures were observed in 5 of 9 PPKS rats but in only 1 of 12 PPKR rats (chi square, p= 0.017). Generalized tonic-clonic (Class V) seizures were not observed. Similar subtle seizures were occasionally observed in uninjured controls (1 of 12 PPKS, 1 of 14 PPKR, 3 of 16 SD). PPKS and PPKR rats also differed in response to PTZ, with longer seizure duration in PKKS rats compared to PPKR rats (50±10s vs. 29±4s, p=0.025, ANOVA). PPKS rats also demonstrated slower postictal return to normal exploratory behavior (589±64s vs. 371±54s, p<0.05, ANOVA). Conclusions: Subtle behavioral seizures consisting of "freezing" or behavioral arrest accompanied generalized spike discharges following CCI-induced TBI in a unique strain of kindling-susceptible rats. The results identify a subtle seizure type manifesting as an outcome of TBI in this strain, suggesting that emergence of post-traumatic epilepsy is influenced by genetic back ground. Kindling-susceptible and kindling-resistant rats may be useful for investigation of mechanisms and genetic background underlying long-term consequences of TBI including PTE and PTSD, and as a screening model for identifying therapies to prevent post-traumatic epileptogenesis.