LOSS OF DEVELOPING CHOLINERGIC BASAL FOREBRAIN NEURONS FOLLOWING EXCITOTOXIC LESIONS OF THE HIPPOCAMPUS - RESCUE BY NEUROTROPHINS

Previous studies have demonstrated that the viability of developing ch olinergic basal forebrain neurons is dependent upon the integrity of n eurotrophin-secreting target cells. In the present study, we examined whether infusions of nerve growth factor (NGF) or brain-derived neurot rophic factor (BDNF) could prevent the loss of cholinergic septal/diag onal band neurons following excitotoxic lesions of their target neuron s within the hippocampus. Postnatal Day 10 rat pups received unilatera l intrahippocampal injections of ibotenic acid. Rats then received int racerebroventricular (icv) injections of nerve growth factor (30 mu g/ injection), brain-derived neurotrophic factor (60 mu g/injection), or saline immediately following the lesion and continuing every third day for 27 days. Both saline- and BDNF-treated rats displayed a significa nt loss of septal/diagonal band neurons expressing the protein and mRN A for choline acetyltransferase (ChAT) and p75 low-affinity nerve grow th factor receptor ipsilateral to the lesion. The magnitude of this lo ss was significantly attenuated in BDNF-treated rats. Many remaining n eurons were atrophic with stunted dendritic processes. In contrast, NG F treatment completely rescued these cells and prevented the shrinkage of remaining cholinergic septal neurons. In addition, both NGF and BD NF induced a sprouting of cholinergic processes within the residual hi ppocampal remnant ipsilateral to the infusions. The present study demo nstrates that icv injections of NGF, and to a lesser extent BDNF, prev ent the loss of developing basal forebrain neurons which occurs follow ing removal of normal target cells. Diffusion studies revealed relativ ely poor penetration of BDNF into brain paren chyma. Thus, it remains to be determined whether the failure of BDNF to provide optimal trophi c support for these cells is biological or due to restricted bioavaila bility of this trophic factor. (C) 1991 Academic Press, Inc.