Neurons of the adult mammalian central nervous system are limited in their ability to regenerate in response to injury. In certain circumstances, however, such neurons can exhibit morphological plasticity (e.g. sprouting). Unilateral transection of the perforant path in the adult rat induces terminal degeneration of entorhinal axons within the molecular layer of the ipsilateral hippocampal dentate gyrus. Cholinergic (and other) afferents subsequently sprout within the denervated zone. We show that despite the breach in the blood-brain barrier at the site of the aspirative lesion, the barrier remains intact in the areas of terminal degeneration (and reinnervation), and peripheral monocytic macrophages do not infiltrate this area to participate in the degenerative and/or regenerative events. Perforant path transection does not induce expression of major histocompatibility antigens on reactive cells within the denervated zone, nor are T lymphocytes recruited to this area. T lymphocyte-deficient Nude rats exhibit normal cholinergic sprouting. Perforant path transection does induce rapid and robust proliferation of microglia, and astrocytes to a lesser extent, in areas undergoing terminal degeneration. Histological evaluation after antimitotic administration shows that this glial proliferation is not required for the subsequent neuronal sprouting events. These results show that the reparative process in this model system involves interactions between cells endogenous to the brain in a non-immune context. Knowledge of these cellular responses provides a framework from which to further investigate putative molecular signals involved in initiating the neuronal sprouting events. Discovering the cellular and molecular interactions taking place under sprouting conditions is likely to be critical for understanding the mechanisms of reactive neuronal growth and, furthermore, may provide insights as to why regeneration is so limited in the central nervous system.