Highly selective effects of nerve growth factor, brain‐derived neurotrophic factor, and neurotrophin‐3 on intact and injured basal forebrain magnocellular neurons

Abstract

Cholinergic neurons of the basal nucleus complex (BNC) respond to nerve growth factor (NGF), the first member of a polypeptide gene family that also includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). NGF, BDNF, and NT-3 are enriched in hippocampus. In addition, NGF and, more recently, BDNF have been shown to stimulate the cholinergic differentiation and enhance the survival of BNC cells in vitro. The present investigation was designed to test, in a comparative fashion, the in vivo effects of human recombinant NGF, BDNF, and NT-3 with confirmed activities in vitro on cholinergic and gamma-aminobutyric acid (GABA)-ergic BNC neurons. The specific questions asked were whether and, to what extent, biologically active recombinant neurotrophins stimulate the transmitter phenotypes of intact cholinergic and GABAergic neurons of the BNC, and whether, and to what extent, recombinant neurotrophins protect the transmitter phenotypes of axotomized cholinergic and GABAergic neurons of the BNC following complete transections of the fimbria-fornix (measured by ChAT enzyme activity and ChAT immunoreactivity and ChAT, p75NGFR, and GAD mRNA hybridization). Our results confirm the profound stimulatory and protective effects of recombinant NGF on the transmitter phenotype of cholinergic BNC neurons at the mRNA and protein levels. The effect of NGF on injured cholinergic neurons of the BNC is very specific and saturated at a dose of 20 micrograms/2 weeks. BDNF appeared to increase moderately p75NGFR expression in both intact and axotomized cholinergic neurons and to exert minor effects on some cholinergic markers (e.g., ChAT immunoreactivity). NT-3 had no effects on cholinergic neurons or the BNC. Moreover, NGF, BDNF, and NT-3 had no influence on GABAergic BNC neurons. Taken together, these results indicate that, despite their significant sequence homologies and their shared abundance in target fields of BNC neurons, NGF, BDNF, and NT-3 show striking differences in their efficacies as cholinergic trophic factors. GABAergic neurons of the BNC are resistant to neurotrophins. The results of the present investigation establish that NGF excels among neurotrophins as a trophic factor for intact and injured basal forebrain cholinergic neurons.