COMPLETE AND SELECTIVE CHOLINERGIC DENERVATION OF RAT NEOCORTEX AND HIPPOCAMPUS BUT NOT AMYGDALA BY AN IMMUNOTOXIN AGAINST THE P75 NGF RECEPTOR

The immunotoxin 192 IgG-saporin, produced by coupling the ribosome-ina ctivating protein saporin to the monoclonal 192 IgG antibody against t he low-affinity p75 NGF receptor (NGFr), was injected into the cerebra l ventricle, septal area, and substantia innominata of adult rats. Inj ections into the cerebral ventricle induced a complete loss of NGFr-po sitive basal forebrain neurons and their axons. Extensive loss of chol inergic neurons was found in the septum, diagonal band, and magnocellu lar preoptic nucleus but not in the nucleus basalis-substantia innomin ata complex, where many cholinergic, presumably NGFr-negative, neurons remained intact. Cholinergic fibers were completely lost in the neoco rtex and hippocampus, showed some preservation in allocortical areas, and showed only minor loss in the amygdala. The NGFr-positive choliner gic basal forebrain neurons progressively degenerated during the first 5 d and did not recover after 180 d. The effect of intraventricular 1 92 IgG-saporin injections on NGFr-positive basal forebrain neurons cou ld be blocked by simultaneous intraventricular injection of colchicine . Intraparenchymal injections into the septal area or substantia innom inata damaged cholinergic neurons mainly around the injection sites an d reduced their respective cortical and hippocampal projections. Nonch olinergic septal neurons containing parvalbumin and noncholinergic neu rons containing calbindin-D-28K or NADPHd, which were adjacent to chol inergic nucleus basalis-substantia innominata neurons, were not affect ed by 192 IgG-saporin. The ChAT immunoreactivity in cortical interneur ons, habenula, and brainstem was unchanged. Dopaminergic and noradrene rgic cortical afferents remained intact. 192 IgG-saporin damaged two n euronal groups outside the basal forebrain that express the p75 NGF re ceptor: NGFr-positive cerebellar Purkinje cells after intraventricular injection and cholinergic striatal interneurons after injections into the substantia innominata. These results indicate that the immunotoxi n 192 IgG-saporin induces a complete and selective lesion of NGFr-posi tive cholinergic basal forebrain neurons projecting to hippocampus and neocortex.