Abstracts

Rationale: It has been suggested that abnormalities in normal postnatal neurogenesis may contribute to seizures and epilepsy. However, the exact role of adult-born neurons is not yet clear. We hypothesized that normal neurogenesis is important in the regulation of excitability, and as a result, abnormal neurogenesis contributes to seizures. To test this hypothesis, we evaluated the response to a convulsant in mice that had normal or reduced neurogenesis. Methods: Two methods were used to reduce neurogenesis (Saxe et al. 2006; Gordon et al. 2010), either focal X-irradiation or an inducible conditional transgenic mouse targeting dividing cells that express the glial fibrillary acid protein (GFAP) promoter. Vanganciclovir administration was used to activate thymidine kinase (TK) in dividing GFAP-expressing cells (GFAP TK+ mice). Reduction of adult neurogenesis was confirmed by staining sections with an antibody to doublecortin. Four to 6 weeks after irradiation, and 1 week after vanganciclovir treatment ended, 4 subdural electrodes were implanted overlying the right occipital cortex and left frontal cortex, with twisted bipolar depth electrodes in each dorsal hippocampus. After 1 week, kainic acid (KA; 6-12 mg/kg, s.c.) was administered. Recordings were conducted for 2 hrs after KA to evaluate seizures. Results: Although KA induced electrographic and convulsive seizure activity in all animals tested (GFAP TK+, n=8; GFAP TK-, n=8; irradiation, n=7; sham irradiation, n=7), the number of generalized electrographic seizures before the first convulsive episode was reduced in GFAP TK+ and irradiated mice (ANOVA; F(3,26)=2.975, p=0.003). Thus, the animals with reduced neurogenesis typically exhibited a stage 3-5 convulsion when their first electrographic seizure occurred, but in controls, the first seizure was typically unassociated with a detectable behavioral change. In other measures, differences were not statistically significant. For example, the mean latency to the first abnormal electrographic event after KA injection was not significant (ANOVA; F(3,26)=0.010, p=0.998). The latency (ANOVA; F(3,26)=1.258, p=0.313), duration (ANOVA; F(3,26)=0.795, p=0.509) and number of generalized electrographic seizures before SE (ANOVA; F(3,26)=2.187, p=0.114) was not different. Conclusions: Our results suggest that adult neurogenesis influences normal excitability because animals with reduced neurogenesis developed KA-induced convulsions more readily than controls. However, this effect appears to be selective because many other indices of seizures were not significantly different.