NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory

Abstract

NMDA receptors (NMDARs) containing NR2A (epsilon1) subunits are key contributors to hippocampal long-term potentiation (LTP) induction in adult animals and have therefore been widely implicated in hippocampus-dependent spatial learning. Here we show that mice lacking the NR2A subunit or its C-terminal intracellular domain exhibit impaired spatial working memory (SWM) but normal spatial reference memory (SRM). Both NR2A mutants acquired the SRM version of the water maze task, and the SRM component of the radial maze, as well as controls. They were, however, impaired on a non-matching-to-place T-maze task, and on the SWM component of the radial maze. In addition, NR2A knock-out mice displayed a diminished spatial novelty preference in a spontaneous exploration Y-maze task, and were impaired on a T-maze task in which distinctive inserts present on the floor of the maze determined which goal arm contained the reward, but only if there was a discontiguity between the conditional cue and the place at which the reward was delivered. This dissociation of spatial memory into distinctive components is strikingly similar to results obtained with mice lacking glutamate receptor-A (GluR-A)-containing AMPA receptors, which support long-term potentiation expression. These results identify a specific role for a NMDAR-dependent signaling pathway that leads to the activation of a GluR-A-dependent expression mechanism in a rapidly acquired, flexible form of spatial memory. This mechanism depends on the C-terminal intracellular domain of the NR2A subunit. In contrast, the ability to associate a particular spatial location with the water maze escape platform or food reward is NR2A independent, as well as GluR-A independent.

Figure 1.

Normal NR2A expression is not required for spatial reference memory in the Morris water maze. A, Mean path length ± SEM during acquisition of the reference memory task for wild-type (○), NR2A^−/− (■), and NR2A^ΔC/ΔC mice (▴). B, Transfer test 1 after 24 trials; mean percentage time ± SEM in the adjacent left (AdjL), training (Tra), adjacent right (AdjR), and opposite (Opp) quadrants. C, Transfer test 2 after 36 trials. WT, Wild-type.

Figure 2.

Normal NR2A expression is required for spatial working memory performance. Rewarded alternation on the elevated T-maze: mean percentages of correct responses ± SEM per block of 10 trials for wild-type (○), NR2A^−/− (■), and NR2A^ΔC/ΔC mice (▴) are shown.

Figure 3.

Within-task demonstration of impaired spatial working memory and spared spatial reference memory performance in NR2A-deficient mice on the radial maze. A, Acquisition phase: mean reference memory errors per trial ± SEM for wild-type (○), NR2A^−/− (■), and NR2A^ΔC/ΔC mice (▴) during 15 blocks (4 trials per block) of training on a three-of-six SRM radial maze task. B, Test phase: working memory errors per trial ± SEM during six blocks of testing on a three-of-six SRM and SWM radial maze task. C, Test phase: reference memory errors per trial ± SEM during six blocks of testing on a three-of-six SRM and SWM radial maze task.

Figure 4.

NR2A knock-out mice display a reduced spatial novelty preference. A discrimination ratio [novel/(novel + other)] was calculated for both the number of arm entries (left) and the time spent in the arms (right) for both wild-type (WT; white bar) and NR2A^−/− mice (gray bar) (chance performance, 0.50).

Figure 5.

Normal NR2A expression is required for performance on a conditional T-maze task, but only if there is a discontiguity between the conditional cue and the place at which the reward is delivered. A, Contiguous task: mean percentage correct responses ± SEM during 14 blocks (10 trials per block) of training on the version of the conditional T-maze task in which the floor inserts are present throughout the entire maze for wild-type (○) and NR2A^−/− (■) mice. B, Discontiguous task: mean percentage correct responses ± SEM during 24 blocks (10 trials per block) of training on the version of the conditional T-maze task in which the floor inserts indicating in which goal arm the milk reward is located are limited to the start arm only.