Four strains of mice were compared regarding their relative abilities to solve the Morris water maze test of spatial memory. Members of the New Zealand Black (NZB) strain revealed steady improvement over the 6 days of training comparable to C57BL/6 mice. The neurotrophin low affinity receptor p75 knockout mouse, in which the binding region is rendered refractory to ligand, displayed profound deficits in the acquisition of this task. Members of the Swiss Webster strain performed intermediate between the poor performance of the p75 mice and the progressively improving learning curves of the NZB and C57 mice. The present results support the notion that interference with functioning of nerve growth factor (NGF) receptors on forebrain cholingergic neurons negatively impacts the animal’s ability to utilize the spatial cues necessary for successful spatial navigation. This effect on NGF receptors was more behaviorally disrupting than the influence of neocortical and hippocampal ectopias as present in the NZB mice. These results support the use of the p75 knockout mouse as a model of forebrain cholinergic neuron dysfunction. On the other hand, these results do not support the use of the NZB mouse as an animal model of human learning disability and dementia.