AbstractRecent studies have demonstrated that mice lacking protein L‐isoaspartate (D‐aspartate) O‐methyltransferase (Pcmt1−/− mice) have alterations in the insulin‐like growth factor‐I (IGF‐I) and insulin receptor pathways within the hippocampal formation as well as other brain regions. However, the cellular localization of these changes and whether the alterations might be associated with an increase in cell number within proliferative regions, such as the dentate gyrus, were unknown. In this study, stereological methods were used to demonstrate that these mice have an increased number of granule cells in the granule cell layer and hilus of the dentate gyrus. The higher number of granule cells was accompanied by a greater number of cells undergoing mitosis in the dentate gyrus, suggesting that an increase in neuronal cell proliferation occurs in this neurogenic zone of adult Pcmt1−/− mice. In support of this, increased doublecortin labeling of immature neurons was detected in the subgranular zone of the dentate gyrus. In addition, double immunofluorescence studies demonstrated that phosphorylated IGF‐I/insulin receptors in the subgranular zone were localized on immature neurons, suggesting that the increased activation of one or both of these receptors in Pcmt1−/− mice could contribute to the growth and survival of these cells. We propose that deficits in the repair of isoaspartyl protein damage leads to alterations in metabolic and growth‐receptor pathways, and that this model may be particularly relevant for studies of neurogenesis that is stimulated by cellular damage. J. Comp. Neurol. 493:524–537, 2005. © 2005 Wiley‐Liss, Inc.