Abstracts

We hypothesize that minimal hippocampal injury following the status epilepticus (SE) is adequate for triggering significant epileptogenesis, and greater levels of hippocampal neurodegeneration and aberrant mossy fiber sprouting (MFS) are not associated with increased frequency of spontaneous recurrent motor seizures (SRMS). To address these issues, we rigorously examined the links between the extent of hippocampal neurodegeneration, the frequency of SRMS and the degree of aberrant MFS after kainic acid (KA)-induced SE in adult male F344 rats. Kainic acid (3 mg/Kg b.w./hr, i.p.) was administered every hr for 3-4 hrs to induce continuous stages III-V seizures for over 3 hrs. Control rats were treated similarly with saline for comparison. Groups of KA-treated and saline-treated rats were euthanized at 4-days post-treatment for neurodegeneration analyses. Additional groups of KA-treated rats were observed continuously for 3 months (6-8 hrs/week; starting from the 3rd month after KA) for the occurrence of SRMS and killed at 5-months post-KA for hippocampal neurodegeneration and aberrant MFS analyses. KA-induced status epilepticus caused bilateral hippocampal injury (HI) in all rats when examined at 4 days post-KA. While a majority (77%) exhibited moderate neurodegeneration in the dentate hilus and the hippocampal CA1 and CA3 subfields, a smaller fraction (23%) exhibited massive neurodegeneration in all of these regions and died within 10 days. All surviving KA-treated rats displayed SRMS at 3-months post-KA and the severity and duration of the SRMS increased over time. Stereological analyses of the surviving neurons at 5-months post-KA revealed two subgroups of rats: one with moderate HI (56%) and another with severe HI (44%). Rats with severe HI exhibited greater level of the aberrant MFS than rats with moderate HI. However, the frequency and duration of SRMS was highly comparable between rats with moderate HI and rats with severe HI. The results suggest that the occurrence of SRMS at extended time-points after the KA-induced SE is consistently associated with significant bilateral hippocampal neurodegeneration and bilateral aberrant MFS. However, the results also underscore that neither the frequency nor the duration SRMS does not increase further with greater levels of hippocampal neurodegeneration and the aberrant MFS. Thus, minimal hippocampal injury after the status epilepticus is adequate for triggering epileptogenesis and SRMS in this rat model of temporal lobe epilepsy. (Supported by grants from National Institute of Neurological Disorders and Stroke (RO1 NS 043507 to A.K.S.), and Department of Veterans Affairs (VA Merit Review Award to A.K.S.).)