192-IMMUNOGLOBULIN G-SAPORIN PRODUCES GRADED BEHAVIORAL AND BIOCHEMICAL-CHANGES ACCOMPANYING THE LOSS OF CHOLINERGIC NEURONS OF THE BASAL FOREBRAIN AND CEREBELLAR PURKINJE-CELLS

Immunolesions of the cholinergic basal forebrain were produced in rats using various intraventricular doses of the immunotoxin 192 immunoglo bulin G-saporin: 0.34, 1.34, 2.0, 2.7 and 4.0 mu g/rat. A battery of b ehavioral tests, chosen on the basis of reported sensitivity to conven tional medial septal or nucleus basalis lesions, was administered. Dos e-dependent impairments were found in acquisition, spatial acuity and working memory in the water maze. Dose-dependent hyperactivity in the open field and in swimming speed was observed. The highest dose group (4.0 mu g) exhibited motoric disturbances which were particularly appa rent in swimming and in clinging to an inclined screen. Response ana h abituation to acoustic startle were diminished in the three higher dos e groups. Histological results from acetylcholinesterase and low-affin ity nerve growth factor receptor staining showed that the lesion was s elective for cholinergic neurons bearing p75 nerve growth factor recep tors in the basal forebrain nuclei. However, some Purkinje cells in th e superficial layers of the cerebellum were also destroyed at the high er doses of immunotoxin. The activity of choline acetyltranferase, use d as a marker of cholinergic deafferentation in regions innervated by the basal forebrain nuclei, was decreased with Increasing doses to a p lateau level of about 90% (average depletion) for the two highest dose groups. These two groups were the only ones to exhibit consistent and severe behavioral impairments on all behavioral tests performed. Thus , for a relatively selective cholinergic basal forebrain lesion, almos t a 90% reduction in choline acetyltransferase activity is needed to p roduce substantial behavioral deficits. It appears that either a consi derable safety factor exists or robust compensatory mechanisms can ame liorate behavioral deficits from a major, but incomplete loss of choli nergic basal forebrain innervation.