Abstracts

Rationale: Prior work has suggested that in the epileptic brain, adult neurogenesis can be abnormal and contribute to epilepsy. Here we document that in the normal adult mouse, with adult-born neurons that integrate and migrate normally, the adult-born neurons protect against seizures. Moreover, they appear to protect against the neuronal loss in the hippocampus that usually follows severe seizures (status epilepticus; SE). Finally, the long-term consequences of SE and neuronal loss, i.e. chronic epilepsy, were reduced: there were fewer chronic seizures. Methods: We used loss-of-function and gain-of-function approaches to reduce and increase adult neurogenesis, respectively in the 6-week-old mice. For loss-of-function, adult neurogenesis was suppressed by pharmacogenetic deletion of dividing radial glial precursors. Mice with herpes simplex virus (HSV)-thymidine kinase (TK) in glial fibrillary acidic protein (GFAP)-expressing progenitor cells (GFAP-TK mice) were used. For gain-of-function, adult neurogenesis was increased by conditional deletion of pro-apoptotic gene Bax in Nestin-expressing progenitors. NestinCreERT2 mice in which tamoxifen-inducible Cre recombinase (CreERT2) is expressed under the control of the rat Nestin promoter (NestinCreERT2Baxf/f mice) were used. SE was induced by pilocarpine at the time when adult-born neurons were up to 6-weeks-old. Three days after SE, neuronal loss was quantified based on Fluoro-Jade C (FJ) staining. SE and chronic seizures were quantified after implanting 4 subdural electrodes prior to SE (over left frontal cortex, right occipital cortex, and bilaterally over dorsal hippocampus). Chronic seizures were monitored 4 weeks after SE for 2-3 weeks continuously by video-electroencephalography. Results: SE had a longer duration (n = 13/group) and SE had more power in mice with reduced neurogenesis relative to controls (n = 7/group; p < 0.05 for both measure). FJ staining in the hippocampus was greater in mice with reduced neurogenesis compared to controls (n = 8-9); these differences were significant in dorsal hilus, area CA1, and ventral hilus (p < 0.05). Conversely, SE was shorter in duration (n = 8-9) and SE had less power in mice with increased neurogenesis compared to controls (n = 7-8; p < 0.05 for both measure). FJ staining in the hippocampus was significantly less in mice with increased neurogenesis compared to controls (n = 10-14); these differences were significant in dorsal hilus, area CA1, and ventral CA3 (p < 0.05). Chronic seizures were significantly reduced in mice with increased neurogenesis relative to controls (n = 3/group; p < 0.05). Chronic seizures were not studied in mice with reduced neurogenesis because long-term survival was poor. Conclusions: These data suggest that normally integrated adult-born neurons, when examined collectively at ages up to 6-weeks-old, exert protective effects against SE, SE-induced neuronal injury in the hippocampus, and chronic seizures.  Funding: National Institutes of Health, Natural Sciences and Engineering Research Council of Canada, New York State Department of Health.