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The Journal of Neuroscience, April 2, 2008, 28(14):3623-3630; doi:10.1523/JNEUROSCI.3639-07.2008

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Behavioral/Systems/Cognitive
NMDA Receptor Subunit NR2A Is Required for Rapidly Acquired Spatial Working Memory But Not Incremental Spatial Reference Memory

David M. Bannerman,¹ Burkhard Niewoehner,¹ Louisa Lyon,¹ Carola Romberg,¹ Wolfram B. Schmitt,¹ Amy Taylor,¹ David J. Sanderson,¹ James Cottam,¹ Rolf Sprengel,² Peter H. Seeburg,² Georg Köhr,² and John N. P. Rawlins¹

¹Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, United Kingdom, and ²Max Planck Institute of Medical Research, Department of Molecular Neurobiology, D-69120 Heidelberg, Germany

Correspondence should be addressed to David M. Bannerman, Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD, UK. Email: david.bannerman{at}psy.ox.ac.uk

NMDA receptors (NMDARs) containing NR2A (1) 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.

Key words: hippocampus; long-term potentiation; synaptic plasticity; water maze; radial maze; T-maze

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Received May 14, 2007; revised Nov. 9, 2007; accepted Dec. 4, 2007.

Correspondence should be addressed to David M. Bannerman, Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD, UK. Email: david.bannerman{at}psy.ox.ac.uk

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