To investigate the role of neuron-target interactions in regulating the survival of developing septo-hippocampal cholinergic neurons, hippocampal neurons were excitotoxically ablated in early postnatal rats. Four weeks after hippocampal ablation, hippocampal levels of brain-derived neurotrophic factor and nerve growth factor (NGF) mRNA had fallen to 15% of control values, and ipsilateral septal levels of NGF protein had fallen to 45% of control values. Four weeks after hippocampal ablation, the number of immunoreactive septal cholinergic neurons had fallen to 30% of control values. The number of cholinergic neurons in the septum correlated significantly with the amount of hippocampal tissue present. Ultrastructural analysis of the septal region at 3 days after hippocampal ablation showed no evidence of excitotoxic damage, but at 7 or 10 days showed degenerative profiles compatible with the delayed cell death of large septal neurons. Two weeks of NGF administration, initiated at 4 weeks after hippocampal lesions, failed to increase the number of detectable cholinergic neurons in the septal region, suggesting that the loss of immunoreactive neurons seen at 4 weeks represented cell death rather than downregulation of cholinergic markers. These findings suggest that septal cholinergic neurons depend for survival during early postnatal development on interactions with hippocampal neurons and are compatible with the possibility that neurotrophins play a role these interactions.