Targeted Immunolesion of Cholinergic Neurons by 192 IgG-Saporin

Abstract

The basal forebrain cholinergic system is known to play an important role in cortical arrousal and normal cognitive function. Cortical cholinergic dysfunction has been implicated in cognitive deficits that occur in Alzheimer’s disease, and the cholinergic projection from the nucleus basalis of Meynert (Nbm) to areas of the cerebral cortex is the pathway that is most early and severely affected in brains from Alzheimer patients. Investigations on the functions of the central cholinergic system require adequate animal models to produce specific cholinergic deficits in vivo. This would allow for a detailed evaluation of the neurochemical, neuropathological, and behavioural sequela as well as functional implications of plastic repair mechanisms following cholinergic hypofunction, and provide information that cannot or only partially be obtained in humans. At present there is no adequate animal model available which could mimic all the biochemical, behavioural, and histopathological abnormalities as observed in patients with Alzheimer’s disease. However, partial success can be achieved with so called “isomorphic models” (1) representing partial parallelism between model and some human conditions. The value of such models is to delineate mechanisms underlying the pathological processes as well as to test for new potential therapeutic strategies. In the last few years an increasing number of studies have applied neurotoxins including excitotoxins or cholinotoxins by stereotaxic injection into the Nbm to produce reductions in cortical cholinergic activity. One of the most serious limitations of these lesion paradigms is the fact that basal forebrain cholinergic neurons are always intermingled with populations of non-cholinergic cells and that the cytotoxins used are far from being selective to cholinergic cells. Recently, a novel approach for neuronal lesioning has been introduced by Wiley et al.(2) by using immunotar-geting of unspecific cytotoxins. Cholinergic neurons of the basal forebrain possess nerve growth factor (NGF) receptors whereas other neurons in this region including the cholinergic cells in the nearby striatum do not express detectable levels of NGF receptors (3,4). It was demonstrated that a well-characterized monoclonal antibody to the low-affinity NGF receptor, 192IgG, accumulates bilaterally exclusively in cholinergic neurons of the basal forebrain following intracerebroventricular administration (see e.g. ref. 5). Employing these properties of 192IgG, a cholinergic immunotoxin was developed by chemical linking of 192IgG to the ribosome inactivating protein saporin (192IgG-saporin; see refs. 2,6; for details of preparation, see ref. 7). Here we demonstrate the usefulness of 192IgG-saporin as a powerful tool for producing an animal model with selective and specific basal forebrain cholinergic lesions in rats which can be applied to study the impact of reduced cortical cholinergic input on neurochemical events in cholinoceptive target regions as well as to test therapetic strategies to compensate for cortical cholinergic dysfunction.