DENTATE GRANULE CELL NEUROGENESIS IS INCREASED BY SEIZURES AND CONTRIBUTES TO ABERRANT NETWORK REORGANIZATION IN THE ADULT-RAT HIPPOCAMPUS

The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throu ghout adult life. In both human temporal lobe epilepsy and rodent mode ls of limbic epilepsy, this same neuronal population undergoes extensi ve remodeling, including reorganization of messy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopi c locations within the dentate gyrus. The mechanistic basis of these a bnormalities, as well as their potential relationship to dentate granu le cell neurogenesis, is unknown. We used a systemic chemoconvulsant m odel of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling t o investigate the effects of prolonged seizures on dentate granule cel l neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in t his model. Pilocarpine-induced status epilepticus caused a dramatic an d prolonged increase in cell proliferation in the dentate subgranular proliferative zone (SGZ), an area known to contain neuronal precursor cells. Colocalization of BrdU-immunolabeled cells with the neuron-spec ific markers turned on after division, 64 kDa, class III beta-tubulin, or microtubule-associated protein-2 showed that the vast majority of these mitotically active cells differentiated into neurons in the gran ule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the denta te gyrus. Furthermore, developing granule cells projected axons aberra ntly to both the CA3 pyramidal cell region and the dentate inner molec ular layer. Induction of hippocampal seizure activity by perforant pat h stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indic ate that prolonged seizure discharges stimulate dentate granule cell n eurogenesis, and that hippocampal network plasticity associated with e pileptogenesis may arise from aberrant connections formed by newly bor n dentate granule cells.