Dentate Granule Cell Neurogenesis Is Increased by Seizures and Contributes to Aberrant Network Reorganization in the Adult Rat Hippocampus

TLDR

In the adult rodent hippocampus, dentate granule cells undergo continuous neurogenesis, yet in temporal lobe epilepsy this population remodels with mossy fiber reorganization, granule cell dispersion, and ectopic placement, and the mechanisms linking neurogenesis to these changes remain unclear. The study aimed to determine how prolonged seizures influence dentate granule cell neurogenesis and whether newly born cells contribute to the network alterations observed in temporal lobe epilepsy. Adult rats received systemic pilocarpine to induce status epilepticus and were labeled with bromodeoxyuridine to track proliferation and differentiation in the subgranular zone, with additional perforant‑path stimulation to compare effects. Seizure activity markedly increased subgranular proliferation, with most BrdU‑positive cells differentiating into neurons that appeared ectopically in the hilus and inner molecular layer and projected aberrant axons to CA3 and the inner molecular layer, indicating that seizures stimulate neurogenesis and that aberrant connections from new granule cells may underlie epileptogenic network plasticity.

Abstract

The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and 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-specific 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 granule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the dentate gyrus. Furthermore, developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer. Induction of hippocampal seizure activity by perforant path stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.