DIFFERENTIAL-EFFECTS ON SPATIAL NAVIGATION OF IMMUNOTOXIN-INDUCED CHOLINERGIC LESIONS OF THE MEDIAL SEPTAL AREA AND NUCLEUS BASALIS MAGNOCELLULARIS

The effects on anatomy and behavior of a ribosomal inactivating protei n (saporin) coupled to a monoclonal antibody against the low-affinity NGF receptor (NGFr) were examined. In adult rats, NGFr is expressed pr edominantly in cholinergic neurons of the medial septal area (MSA), di agonal band nuclei, and nucleus basalis magnocellularis (nBM), but als o in noncholinergic cerebellar Purkinje cells. Rats with immunotoxin i njections to the MSA, nBM, and lateral ventricle were compared to cont rols on a spatial and cued reference memory task in the Morris maze. T oxin injections to the MSA slightly impaired the initial, but not asym ptotic, phase of spatial navigation. injections to the nBM impaired al l phases of spatial navigation. Cued navigation, however, was not affe cted in either the MSA or nBM group. The ventricular injections severe ly affected spatial and cued navigation. Acetylcholinesterase (AChE) h istochemistry and NGFr and choline acetyltransferase immunohistochemis try revealed a loss of(l)almost all NGFr-positive cholinergic neurons in the MSA and AChE fibers in hippocampus (MSA group); (2) almost all NGFr neurons in the nBM, some in the MSA, most AChE fibers in neocorte x and some in the hippocampus (nBM group), and (3) almost all NGFr neu rons in the MSA and nBM and their corresponding hippocampal and cortic al AChE fibers (ventricular group). Cholinergic nBM projections to the amygdala were largely preserved in all groups. The amount of choliner gic fiber loss in the cortex correlated modestly, but significantly, w ith the severity of impairment of the asymptotic phase of performance of the spatial task. An unambiguous interpretation of the anatomical l ocus of behavioral deficits was not possible because of damage to chol inergic striatal interneurons (nBM group) and to noncholinergic cerebe llar Purkinje cells (ventricular group). These data suggest that the c holinergic,cortical system is critical to the performance of this spat ial memory task. Cholinergic denervation of the hippocampus alone, how ever, is not sufficient to impair markedly performance of this task.