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Journal of Neuroscience, Vol 14, 1271-1289, Copyright © 1994 by Society for Neuroscience
Complete and selective cholinergic denervation of rat neocortex and hippocampus but not amygdala by an immunotoxin against the p75 NGF receptor
S Heckers, T Ohtake, RG Wiley, DA Lappi, C Geula and MM Mesulam
Bullard Laboratory, Department of Neurology, Beth Israel Hospital, Boston, Massachusetts 02215.
The immunotoxin 192 IgG-saporin, produced by coupling the ribosome-
inactivating protein saporin to the monoclonal 192 IgG antibody against the
low-affinity p75 NGF receptor (NGFr), was injected into the cerebral
ventricle, septal area, and substantia innominata of adult rats. Injections
into the cerebral ventricle induced a complete loss of NGFr-positive basal
forebrain neurons and their axons. Extensive loss of cholinergic neurons
was found in the septum, diagonal band, and magnocellular preoptic nucleus
but not in the nucleus basalis- substantia innominata complex, where many
cholinergic, presumably NGFr- negative, neurons remained intact.
Cholinergic fibers were completely lost in the neocortex and hippocampus,
showed some preservation in allocortical areas, and showed only minor loss
in the amygdala. The NGFr-positive cholinergic basal forebrain neurons
progressively degenerated during the first 5 d and did not recover after
180 d. The effect of intraventricular 192 IgG-saporin injections on
NGFr-positive basal forebrain neurons could be blocked by simultaneous
intraventricular injection of colchicine. Intraparenchymal injections into
the septal area or substantia innominata damaged cholinergic neurons mainly
around the injection sites and reduced their respective cortical and
hippocampal projections. Noncholinergic septal neurons containing
parvalbumin and noncholinergic neurons containing calbindin- D28k or
NADPHd, which were adjacent to cholinergic nucleus basalis- substantia
innominata neurons, were not affected by 192 IgG-saporin. The ChAT
immunoreactivity in cortical interneurons, habenula, and brainstem was
unchanged. Dopaminergic and noradrenergic cortical afferents remained
intact. 192 IgG-saporin damaged two neuronal groups outside the basal
forebrain that express the p75 NGF receptor: NGFr- positive cerebellar
Purkinje cells after intraventricular injection and cholinergic striatal
interneurons after injections into the substantia innominata. These results
indicate that the immunotoxin 192 IgG-saporin induces a complete and
selective lesion of NGFr-positive cholinergic basal forebrain neurons
projecting to hippocampus and neocortex.
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