Requirement for Hippocampal CA3 NMDA Receptors in Associative Memory Recall

TLDR

Pattern completion, the ability to retrieve complete memories from incomplete cues, is a key function of biological memory systems, and the CA3 region of the hippocampus, with its extensive recurrent connectivity, has been proposed to support this function. The study aimed to test whether CA3 NMDA receptors are required for pattern completion by examining memory recall in mice lacking these receptors. To test this, the authors created a genetically engineered mouse strain with a selective ablation of the NMDA receptor gene in adult CA3 pyramidal cells and analyzed its performance. The CA3‑NMDA‑deficient mice acquired and retrieved spatial memory normally with full cues but were impaired when only partial cues were presented, and CA1 place cell activity was reduced under partial cue conditions, demonstrating that CA3 NMDA receptors are essential for associative memory recall.

Abstract

Pattern completion, the ability to retrieve complete memories on the basis of incomplete sets of cues, is a crucial function of biological memory systems. The extensive recurrent connectivity of the CA3 area of hippocampus has led to suggestions that it might provide this function. We have tested this hypothesis by generating and analyzing a genetically engineered mouse strain in which the N-methyl-D-asparate (NMDA) receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall.