Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive beta-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze, hAPP mice are impaired before and after amyloid plaque deposition. Here we show, using a new water-maze training protocol, that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with beta-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that A beta overexpression and/or A beta plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.

Reconsolidation is a putative neuronal process in which the retrieval of a previously consolidated memory returns it to a labile state that is once again subject to stabilization. This study explored the idea that reconsolidation occurs in spatial memory when animals retrieve memory under circumstances in which new memory encoding is likely to occur. Control studies confirmed that intrahippocampal infusions of anisomycin inhibited protein synthesis locally and that the spatial training protocols we used are subject to overnight protein synthesis-dependent consolidation. We then compared the impact of anisomycin in two conditions: when memory retrieval occurred in a reference memory task after performance had reached asymptote over several days; and after a comparable extent of training of a delayed matching-to-place task in which new memory encoding was required each day. Sensitivity to intrahippocampal anisomycin was observed only in the protocol involving new memory encoding at the time of retrieval.

To assess the interaction between spatial and procedural memory systems, the authors developed a learning protocol in the water maze using a rising "Atlantis" platform that requires rats to learn to swim to a specific location and, once there, to learn a "dwelling" response to raise the platform. In this protocol, the effects of temporal inactivation of the dorsal hippocampus with the AMPA/kainate receptor antagonist LY326325 on different memory phases were investigated. Hippocampal inactivation impaired acquisition of the searching task, mainly because of disruption of procedural learning. Inactivation also impeded consolidation and retrieval of spatial information, while leaving expression of dwelling responses intact. These findings challenge the idea of a sharp demarcation between spatial and procedural learning with respect to hippocampal involvement.

Spatial pretraining can enable spatial learning in another environment that ordinarily requires hippocampal N-methyl-d-aspartate (NMDA) receptor activity to become independent of that activity. This study explored further the circumstances in which this training-induced 'rescue' of later learning in the presence of the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (D-AP5) can occur. D-AP5 (0, 10, 20 and 30 mm in artificial cerebrospinal fluid) was infused continuously (0.5 μL/h, from a minipump) and bilaterally into the dorsal hippocampus during spatial-reference-memory training in a watermaze (4 trials/day, 8 days). This was preceded either by handling only or by identical spatial training in another watermaze in a separate laboratory with different extramaze cues. In naïve rats, D-AP5 caused a dose-related impairment in spatial reference memory acquisition that was significant at the lowest 5 nm/h infusion concentration. In pretrained rats, the dose-response function was shifted such that, in watermaze 2, spatial learning was normal at this low concentration, with a deficit at higher infusion concentrations. The induction of long-term potentiation in the dentate gyrus in vivo was blocked at all D-AP5 concentrations. Sensorimotor abnormalities sometimes seen with NMDA receptor antagonists were only apparent at the highest concentration. The implication of this paradoxical dissociation between hippocampal NMDA receptor-dependent plasticity and spatial learning is discussed with reference to two rival hypotheses of the impact of pretraining.