Hippocampal neurogenesis follows kainic acid-induced apoptosis in neonatal rats

The effects of kainic acid (KA) on neurogenesis in the developing rat hippocampus were investigated. Neonatal [postnatal day (P) 7] rats received a single bilateral intracerebroventricular infusion of KA (50 nmol in 1.0 microl) or vehicle. At P14, P25, P40, and P60, the spatial and temporal relationships between the neurodegeneration and neurogenesis induced by KA were explored using terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) to detect the dying cells and 5-bromodeoxyuridine (BrdU) to label newly generated cells. There was progressive loss of neurons in the cornu ammonis (CA) 1 and CA3 subfields of the hippocampus at all time points in KA-treated rats. TUNEL staining identified dying cells at P14 through P60, mainly in the CA3 subfield. The number of TUNEL-positive cells decreased with age. Neurogenesis also was observed in the KA-treated hippocampus. The number of BrdU-positive cells in the dentate gyrus was significantly decreased at P14, when the number of TUNEL-positive cells is highest. However, at later time points (P40 and P60) the number of BrdU-positive cells in the dentate gyrus was significantly increased. In addition, the number of BrdU-positive cells was increased in the CA3 subfield at P40 and P60 in KA-treated rats. A substantial proportion (40%) of the newly generated cells in CA3 also expressed markers of immature and mature neurons (class III beta-tubulin and neuronal nuclei). Newly generated cells in the CA3 subfield only rarely expressed glial markers (8%). These results suggest that a single exposure to KA at P7 has both immediate (inhibition) and delayed (stimulation) effects on neurogenesis within the dentate gyrus of developing rats. KA administration resulted in both neuronal apoptosis and neurogenesis within the CA3 subfield, suggesting that the purpose of neurogenesis in the CA3 is to replace neurons lost to apoptosis.