In order to determine whether granule cell death stimulates the proliferation of granule cell precursors in the dentate gyrus of the adult rat, we performed both excitotoxic and mechanical lesions of the granule cell layer and examined the numbers of proliferating cells at different survival times. Using [³H]thymidine autoradiography, bromodeoxyuridine labelling and proliferating cell nuclear antigen immunohistochemistry, we observed an increase in proliferating cells on the lesioned side compared to the unlesioned side 24h after surgery. A significant positive correlation between the extent of granule cell damage and the number of proliferating cells was observed. Combined [³H]thymidine autoradiography and immunohistochemistry for cell-specific markers revealed that the vast majority of proliferating cells had the morphological characteristics of granule cell precursors and were not immunoreactive for vimentin, a marker of immature glia. Combined [³H]thymidine autoradiography and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling for degenerating cells showed that the proliferating cells did not rapidly degenerate. Three weeks after the lesion, most cells produced in response to the lesion had the morphological characteristics of mature granule neurons, were located in the granule cell layer and expressed markers of mature granule neurons, including neuron-specific enolase, the N-methyl-d-aspartate receptor subunit NRI and calbindin. These findings suggest that granule cell death stimulates the proliferation of precursor cells, many of which survive and differentiate into mature granule neurons.