Abstracts

Rationale: The generation of new granule neurons in the postnatal mammalian hippocampus is exquisitely sensitive to both physiological and pathological stimulation. Animal models of temporal lobe epilepsy (TLE) display an enhanced rate of new neuron production. While it is tempting to speculate the functional implications of postnatal neurogenesis after seizures, it is unclear whether the increased neurogenesis is reparative, or alternatively, contributes to recurrent seizures. Methods: To begin to address the functional role of seizure-induced neurogenesis, we have utilized a genetic mouse model that exhibits a dramatic reduction of postnatal hippocampal neurogenesis upon stem cell-specific deletion of NeuroD, an essential neurogenic transcription factor. Results: Kainic acid-induced seizures increase the number and maturation of new neurons, however this is significantly reduced in NeuroD conditional knockout mice, suggesting that NeuroD is required for seizure-induced neurogenesis. In contrast, NeuroD deficiency does not appear to block exercise-induced neurogenesis, a more physiological scenario. Conclusions: Together these results suggest: 1) that adult hippocampal neurogenesis is context-dependent, 2) the presence of multiple pathways underlying neurogenesis in response to various stimuli, and 3) that NeuroD regulation may represent a cell-intrinsic mechanism that distinguishes between different pathways. We are currently conducting functional and mechanistic studies in NeuroD conditional knockout mice after seizure induction. Our studies will help contribute to the emerging concept that stem/progenitor cells in the postnatal hippocampus “sense” different forms of activity for their developmental progression.