Cholinergic sprouting in the hippocampus: a proposed role for IL-1

Damage to the entorhinal afferents (i.e., perforant path) to the hippocampal dentate gyrus leads to sprouting of the remaining intact septal cholinergic afferents within the denervated outer molecular layer. To investigate the cellular and molecular events which may contribute to this sprouting response, we describe the temporal sequence of cellular changes in the denervated zone prior to the observed neural reorganization. Rats were given perforant path (PP) transections and sacrificed at various time points following the lesion, on Days (D) 1, 2, 3, 4, 5, 6, and 30. Coronal sections at the level of the dorsal hippocampus were immunostained to localize microglia (OX-42), interleukin-1 (IL-1), and astroctytes (GFAP). We observed a rapid increase in the number of immunoreactive microglia in the denervated molecular layer within the first day following PP transection. Parallel sections show a concomitant increase in the number of IL-1-positive cells. Maximal reactive changes (i.e., hypertrophy and increase in number) in GFAP-positive astrocytes are not observed until D5. This time course of events suggests a role of microglia in astrocyte activation in vivo via production of IL-1 and offers support for a proposed hypothesis postulating a cascade of glial events which may lead to cholinergic sprouting following PP transection.