Abstracts

Status epilepticus (SE) considerably enhances dentate neurogenesis during the early post-SE period, whereas the spontaneous recurrent motor seizures (SRMS) dramatically diminish dentate neurogenesis during chronic epilepsy (Hattiangady et al., Neurobiol. Dis., 17:473-490, 2004). However, the extent of long-term survival of new neurons added to the dentate granule cell layer (GCL) at both early and delayed time-points after the SE are mostly unknown. Therefore, we evaluated the enduring survival of new neurons added to the GCL during the first 12 days after the SE and during chronic epilepsy. Young adult male F344 rats were treated every hr with Kainic acid (KA) for 3-4 hours (3 mg/Kg b.w./hr, i.p.). This induced continuous stages III-V seizures (SE) for over 3 hrs. Newly generated cells and neurons at both early post-SE (the first 12 days after the SE) and delayed post-SE (12 days during the 5th month after the SE) were labeled using daily injections of 5[apos]-bromodeoxyuridine (BrdU; 100 mg/Kg bw). Age-matched control rats received similar BrdU injections. Groups of BrdU injected rats were killed at 24 hrs after the last BrdU injection for analyses of the newly born cells/neurons using BrdU immunostaining, BrdU-doublecortin or BrdU-NeuN dual immunofluorescence, and the optical fractionator cell counting method. Additional groups of rats were killed at 3-5 months post-BrdU injections for analyses of the long-term survival of newly born cells/neurons. All KA-treated rats displayed significant SRMS during the survival period. Quantification of the numbers of new cells and neurons revealed that 40-50% of new neurons added to the GCL during the early post-SE exhibit enduring survival. This is strikingly similar to the survival of new neurons observed in the age-matched intact rats. Interestingly, the survival of new neurons added to the GCL during the chronic epilepsy phase was also comparable to the survival of newly born neurons in the age-matched intact rats (40-50%). A sizable fraction of new neurons generated shortly after the SE exhibit protracted survival, implying that the new granule cells added to the GCL at early post-SE likely contribute to epileptogenesis. Further, a dramatically declined dentate neurogenesis during chronic epilepsy is a result of decreased production of new cells rather than the diminished survival of newly differentiated neurons. Decreased production could be due to significant changes in the stem cell number and/or the microenvironment of the stem/progenitor cells during chronic epilepsy. The dramatic decrease in dentate neurogenesis during chronic epilepsy likely contributes to the hippocampal-dependent learning and memory deficits. (Supported by grants from the NINDS (RO1 NS 043507 to A.K.S.) and NIA (RO1 AG20924 to A.K.S.).)