Spatial memory impairment in mice with immunotoxic lesions of the cholinergic basal forebrain

Abstract

Degeneration of the cholinergic basal forebrain (CBF) is a feature of Alzheimer's disease (AD) that correlates with dementia severity. This correlation has motivated investigators to develop animal models of AD by lesioning the CBF. We tested the hypothesis that mu‐p75‐saporin creates cholinergic lesions in mice and that these lesions result in deficits in spatial cognition. C57BL/6J mice received intraventricular injection of either a high (4 μg) or low (2 μg) dose of mu‐p75‐saporin and were tested in the Morris water maze. Mice receiving 4 μg showed increased latency to find the hidden platform during training. This increased latency was confounded by motor deficits because impairments in swim speed were observed. In a probe trial, mice receiving 4 μg swam a greater average distance from the platform location than saline‐treated mice. Mice receiving 2 μg showed increased latency to find the platform with no confounding effect on swim speed. In a probe trial, mice receiving 2 μg swam with similar proximity to the platform location as saline‐treated mice. Staining of the brains for acetylcholinesterase, p75, and parvalbumin showed that the treated animals had specific lesions of the CBF. In summary, features of Alzheimer's disease can be modeled in mice using mu‐p75‐ saporin, but higher doses produce confounds in motor ability.