Complete and selective cholinergic denervation of rat neocortex and hippocampus but not amygdala by an immunotoxin against the p75 NGF receptor

Stephan Heckers*, Toshiyuki Ohtake, Ronald G. Wiley, Douglas A. Lappi, Changiz Geula, Marek Marsel Mesulam

*Corresponding author for this work

Research output: Contribution to journalArticle

364 Scopus citations

Abstract

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 D(28K) 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.

Original languageEnglish (US)
Pages (from-to)1271-1289
Number of pages19
JournalJournal of Neuroscience
Volume14
Issue number3 I
DOIs
StatePublished - Mar 1994

Keywords

  • AChE histochemistry
  • ChAT
  • NGF receptor
  • immunohistochemistry

ASJC Scopus subject areas

  • Neuroscience(all)

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