EFFECTS OF NEONATAL LESIONS OF THE BASAL FOREBRAIN CHOLINERGIC SYSTEMBY 192-IMMUNOGLOBULIN-G-SAPORIN - BIOCHEMICAL, BEHAVIORAL AND MORPHOLOGICAL CHARACTERIZATION

Selective removal of the basal forebrain cholinergic neurons by the im munotoxin 192 immunoglobulin G-saporin has offered a new powerful tool for the study of the relationships between cholinergic dysfunction an d cognitive impairments. In the present study the morphological and fu nctional consequences of selective lesions of the basal forebrain chol inergic system during early postnatal development have been investigat ed following bilateral intraventricular injections of 192 immunoglobul in G-saporin to immature (four-day-old) rats. Administration of increa sing doses (0.2-0.8 mu g) of the immunotoxin produced dose-dependent l oss of cholinergic neurons in the septal/diagonal band area (up to 72- 86%) and in the nucleus basalis magnocellularis (up to 91-93%), parall eled by marked reductions in choline acetyltransferase activity in the hippocampus and several cortical regions (73-84%). The parvalbumin-po sitive neurons in the septal/diagonal band area and the calbindin-posi tive Purkinje cells in the cerebellum were unaffected at all dose leve ls. Brain dopamine or noradrenaline levels were unaffected or increase d by the immunotoxin treatment. At the optimal dose, 0.4 mu g, the tox in conjugate produced maximal cholinergic depletion without significan t mortality. Higher doses (0.8, 1.2 and 1.6 mu g) of toxin, on the oth er hand, proved to be lethal for most or all of the injected animals. When tested at three and eight months after the optimal dose, in spite of persisting cholinergic depletion, the noenatally lesioned animals showed no impairment in the water maze task or in locomotor activity a nd exploration as compared to normal controls, probably reflecting par tial sparing of the cholinergic neurons by the neonatal immunotoxic le sion (above all in the vertical and horizontal limbs of the diagonal b and area), and/or a greater degree of plasticity in the developing as compared to the mature cholinergic system. The place navigational perf ormance of the neonatally lesioned animals in the water maze task was abolished by central muscarinic cholinergic receptor blockade (by atro pine) or by a second immunotoxic lesion, which eliminated virtually al l residual cholinergic neurons in the septal/diagonal band area and th e nucleus basalis. Administration of 192 immunoglobulin G-saporin to s imilarly trained, but previously normal adult rats, produced similar c holinergic depletions but much less severe place navigation deficits, suggesting that preoperative training on the task may reduce the funct ional consequences of a subsequent cholinergic lesion. The results thu s support the view that the basal forebrain cholinergic system may be implicated in the acquisition rather than retention of spatial memory in the water maze task. Copyright (C) 1996 IBRO.