ENDOGENOUS FGF-2 IS IMPORTANT FOR CHOLINERGIC SPROUTING IN THE DENERVATED HIPPOCAMPUS

To investigate the molecular mechanisms of cholinergic sprouting in th e hippocampus after removal of entorhinal cortical inputs, we evaluate d trophic factor gene expression in the denervated hippocampus. Despit e the proposed role for nerve growth factor (NGF) in this sprouting, w e observed no change in NGF mRNA or protein at several postlesion time points. In contrast, FGF-2 mRNA was increased within 16 hr. FGF-2 imm unoreactivity was localized within GFAP-positive hypertrophic astrocyt es distributed specifically within the denervated outer molecular laye r after the lesion. To address the functional significance of this inc rease in FGF-2, we assessed the magnitude of cholinergic sprouting in animals receiving chronic intracerebroventricular infusions of neutral izing antibodies specific for FGF-2 and compared it with that observed in lesioned animals receiving infusate controls. Animals given FGF-2 antibodies displayed a marked reduction in cholinergic sprouting as co mpared with controls. In fact, many of these animals exhibited virtual ly no sprouting at all despite histological verification of complete l esions. These results suggest that endogenous FGF-2 promotes cholinerg ic axonal sprouting in the injured adult brain. Furthermore, immunocyt ochemical localization of receptors for FGF-2 (i.e., FGFR1) on project ing basal forebrain cholinergic neurons suggests that FGF-2 acts direc tly on these neurons to induce the lesion-induced sprouting response.