Differences in spatial learning comparing transgenic p75 knockout, New Zealand Black, C57BL/6, and Swiss Webster mice.

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.

Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases.

The formation of spatial memory appears to be dependent upon an intact hippocampus capable of the specific biochemical changes associated with synaptic remodeling. Hippocampal damage results in the disruption of synaptic remodeling and the acquisition of spatial memory tasks. Ethanol also disrupts normal hippocampal functioning and spatial memory. The present investigation established a dose-response relationship between ethanol treatment and impairment of spatial memory as measured using the circular water maze task. Intraperitoneal ethanol doses of 1.5 and 2 g/kg significantly increased the latency and distance swam to find the submerged pedestal as compared with a 1 g/kg dose, and 0.15 M NaCl vehicle control treatments. On days 2, 4, and 6 of acquisition animals were sacrificed and brain tissues were retained from the hippocampus, prefrontal neocortex, and cerebellum for measurement of matrix metalloproteinases (MMPs). The results indicated that ethanol treatment interfered with MMP-9, but not MMP-2, activity in the hippocampus, and to a lesser degree in the prefrontal cortex. No changes in the cerebellum were measured. Elevations in MMP activity appear to be a prerequisite to reconfiguration of extracellular matrix cell adhesion molecules thought to be important in the process of synaptic plasticity, which in turn appears to be necessary for memory consolidation. Thus, ethanol-induced impairment in the acquisition of spatial memory tasks may, in part, be due to disruption of brain MMP activity.