Atrophy but not death of adult septal cholinergic neurons after ablation of target capacity to produce mRNAs for NGF, BDNF, and NT3

Abstract

The effect of unilateral excitotoxic ablation of hippocampal neurons was investigated on (1) the local production of mRNA for NGF and related neurotrophins, (2) the amount of NGF protein in the septal region, and (3) the viability and appearance of afferent septal cholinergic neurons in adult rats. After near complete ablation of hippocampal neurons, total levels of NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3) mRNA measured by quantitative Northern blot analysis in the hippocampal remnant fell significantly, to less than 25% of control values by 28 d and to less than 9% by 300 d. In the septal region ipsilateral to such lesions, NGF protein levels measured by ELISA fell significantly, to about 35% of control values, but the number of immunohistochemically detected cholinergic neurons did not decline significantly for up to 500 d. Instead, the cholinergic neurons persisted in an atrophied state, exhibiting severe shrinkage and reduced staining for the transmitter-synthesizing enzyme ChAT. The parameters of cell size and ChAT staining intensity correlated significantly with the amount of hippocampal tissue present. These findings indicate that in adult rats, target-derived NGF, BDNF, and NT3 do not regulate the survival of septal cholinergic neurons in proportion to the number of target neurons present. Moreover, the findings suggest that one or more of these target-derived neurotrophins regulate the structural and chemical phenotype of these neurons in the adult.