To investigate whether the ageing process might affect neuron-target interactions which influence the phenotype of septal cholinergic neurons, we compared the response of these neurons to partial loss of target tissue in young adult and aged animals. Groups of young adult (four to six months) or aged (24-33 months) male Sprague-Dawley rats received unilateral infusions into the hippocampus of either the excitotoxic amino acid N-methyl-D-aspartate, or vehicle. The resulting excitotoxic lesions reduced the mean cross-sectional area of the hippocampus by 55-60%. Ipsilateral septal cholinergic neurons immunohistochemically stained for either choline acetyltransferase or low-affinity neurotrophin receptor (p75NTR) were morphometrically evaluated. In young adult rats with partial hippocampal lesions, the number and staining intensity of ipsilateral septal cholinergic neurons were not significantly different from age-matched control values, but these cholinergic neurons exhibited a significant 12% reduction in cross-sectional area. In aged rats with hippocampal lesions of equivalent size, ipsilateral cholinergic neurons showed a significant 29% reduction in cross-sectional area, a significant 19% reduction in choline acetyltransferase staining intensity as measured by densitometry, and a significant 21% reduction in the number of choline acetyltransferase- but not p75NTR-stained septal neurons, as compared with age-matched control animals. These findings show that in aged rats, septal cholinergic neurons atrophy more severely in response to the partial loss of their target neurons than in young adult rats, in the form of pronounced cell shrinkage and down-regulation of intracellular levels of the transmitter-synthesizing enzyme, choline acetyltransferase, in some cases to the point of the absence of detectable staining for this marker in some cells. The continued detection of p75NTR indicates that significant neuronal cell death did not take place. These findings suggest that basal forebrain cholinergic neurons have an increased vulnerability to disturbances of neuron-target interactions in aged animals, which may contribute to the degenerative changes exhibited by these cholinergic neurons in ageing and age-related conditions such as Alzheimer's disease.