Persistent innervation of the rat neocortex by basal forebrain cholinergic neurons despite the massive reduction of cortical target neurons. II. Neurochemical analysis.
A significant reduction in the activity of cholinergic enzymes in the neocortex is one of the characteristic neurochemical abnormalities in Alzheimer's disease. The withdrawal of cholinergic innervation is thought to be due to atrophy and degeneration of the cholinergic neurons of the basal forebrain, postulated to occur as a consequence of the loss of postsynaptic target neurons and trophic factors synthesized by these target cells. To directly test the dependence of basal forebrain cholinergic innervation on the presence of target neurons, pregnant rats were administered moderate doses of methylazoxymethanol acetate on Gestational Days 14 and 15. This results in a 40-70% reduction of cortical neurons in offspring of treated dams, but has no significant effect on the genesis of basal forebrain cholinergic neurons. In this paper, neurochemical analysis of cholinergic enzymes (ChAT and AchE) in 2-month-old offspring reveals that the basal forebrain innervates the hypocellular cortex in apparently normal fashion, despite the loss of target neurons. The cholinergic innervation of basal forebrain target regions was examined at various times through 20 months of age and was found to retain the initial high levels of enzymatic activity, without any evidence of loss of cholinergic innervation. The preservation of cholinergic innervation over 20 months despite the massive loss of target neurons contradicts the theory of dependence of basal forebrain cholinergic neurons on target-derived trophic support. These results suggest that the degeneration of basal forebrain cholinergic neurons in Alzheimer's disease is due to phenomena more complex than a reduction in the availability of trophic factors.
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461.
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Davies
D000110:Acetylcholinesterase / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D001921:Brain / Q000033:anatomy & histology* / Q000187:drug effects / Q000254:growth & development; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000187:drug effects; D005865:Gestational Age; D008746:Methylazoxymethanol Acetate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011247:Pregnancy; D016548:Prosencephalon / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D013004:Somatostatin / Q000378:metabolism*
D013004:Somatostatin; D008746:Methylazoxymethanol Acetate; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase