Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice

Abstract

The selective lesion of basal forebrain cholinergic neurons (BFCNs) is an unestimable tool to study the implication of these neurons in cognition, an interest widely motivated by their degeneration in Alzheimer's disease. Here we evaluated the histochemical and behavioral effects of a selective lesion of BFCNs in C57BL/6J mice treated intracerebroventricularly (ICV) with a novel version of the immunotoxin mu p75-saporin (0.4 mug/mouse). There was a 100% postsurgical survival rate, no abnormal loss of weight, no disruption of sensorimotor coordination, and no noncognitive bias in a water-maze test. This immunotoxin induced a loss of choline acetyltransferase-positive neurons in the medial septum (-82%) and in the nucleus basalis (-55%). Preserved parvalbumine-immunostaining suggests that the lesion was specific to BFCNs. Septo-hippocampal and basalo-cortical projections of BFCNs degenerated as suggested by massive loss of acetylcholinesterase-positive staining in the hippocampus and the cortical mantle. Moreover, anticalbindin immunostaining showed no damage to cerebellar Purkinje cells. Lesioned mice displayed increased diurnal and nocturnal locomotor activity. Their spatial learning/memory performances in a water maze and in a Barnes maze were significantly impaired: learning was substantially slowed down, although not obliterated, and memory retention was altered. These behavioral consequences are comparable, with fewer side effects, to those reported after ICV 192 IgG-saporin in rats. In conclusion, the new version of mu p75-saporin provides a safe and powerful tool for BFCN lesion in mice.