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Abstract

Genetically modified mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit, GluR-A (GluR1), and deficient in hippocampal CA3-CA1 long-term potentiation (LTP), were assessed on a novel, hippocampal-dependent spatial reference memory, paddling pool escape task. The mice were required to use the extramaze cues around the laboratory to find a hidden escape tube that was in a constant location at one of 12 possible positions around the perimeter of the paddling pool, in order to escape from shallow water. The knockout mice performed well on this task. They displayed a small initial impairment (in terms of both escape latencies and choice errors), but they were soon as efficient as the wild-type mice in escaping from the water. This was further demonstrated by performance during a 20-s probe trial in which the exit tube was blocked. Both groups of mice spent most of the time searching in the quadrant of the pool in which the exit tube had previously been located. In a subsequent experiment, entirely normal spatial acquisition was observed in the knockout mice when the paddling pool was moved to a novel spatial environment. The GluR-A -/- mice were also unimpaired in a further reversal phase in which the correct exit location was moved by 180 degrees around the perimeter wall. These results are consistent with previous watermaze studies, providing further demonstration of intact hippocampus-dependent spatial reference memory in GluR-A knockout mice. They contrast strikingly with the profound deficits in hippocampus-dependent, short-term, flexible spatial working memory observed in these knockout mice. This study also demonstrates a novel behavioral task for assessing spatial memory in genetically modified mice. This task shares the behavioral profile of the well-established watermaze paradigm, but may have advantages for the study of genetically modified mice.