LEARNING IMPAIRMENTS FOLLOWING INJECTION OF A SELECTIVE CHOLINERGIC IMMUNOTOXIN, ME20.4 IGG-SAPORIN, INTO THE BASAL NUCLEUS OF MEYNERT IN MONKEYS

Four groups of monkeys (Callithrix jacchus) were injected with saline or increasing amounts of the immunotoxin, ME20.4 IgG-saporin, directly into the basal nucleus of Meynert via a frontal trajectory which avoi ded damage to the overlying basal ganglia. ME20.4 IgG binds to the pri mate p75 low-affinity neurotrophin receptor; when the saporin deriviti zed antibody is injected into the basal forebrain, it selectively dest roys the magnocellular neurons of the basal nucleus of Meynert which a re the cells of origin of the cholinergic projection to the neocortex. The highest dose of ME20.4 IgG-saporin produced a significant impairm ent on acquisition of a perceptually difficult visual discrimination. There was no significant effect on retention of tasks learnt before or after surgery, nor on concurrent acquisition of several perceptually easy discriminations or serial reversal of an easy discrimination. The se results suggest that the impairment is not due to visual, motor or motivational difficulties and does not consist of difficulties with th e formation of reward associations. Rather the impairment is largely c onfined to acquisition of perceptual discriminations. There was a sign ificant correlation between the density of ME20.4 immunostaining in th e basal nucleus of Meynert and the density of acetylcholinesterase his tochemical staining in the frontal and temporal cortex and an inverse correlation between both of these and the degree of learning impairmen t in the animals. Lesioned animals also showed significant impairment on acquisition and reversal of perceptually easy discriminations when treated with a dose of scopolamine which did not impair performance in control animals. These results provide further evidence that cortical cholinergic neurotransmission contributes to certain forms of learnin g. The availability of a selective cholinergic immunotoxin effective i n primates provides an important new tool for the study of cholinergic function and its involvement in ageing, Alzheimer's disease and other pathological states. (C) 1997 IBRO. Published by Elsevier Science Ltd .