• Jonathan L Brigman, Tara Wright, Giuseppe Talani, Shweta Prasad-Mulcare, Seiichiro Jinde, Gail K Seabold, Poonam Mathur, Margaret I Davis, Roland Bock, Richard M Gustin, Roger J Colbran, Veronica A Alvarez, Kazu Nakazawa, Eric Delpire, David M Lovinger, and Andrew Holmes.
• Sections on Behavioral Science and Genetics, Synaptic Pharmacology, and Neuronal Structure, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852, USA. brigmanj@mail.nih.gov
• J. Neurosci. 2010 Mar 31;30(13):4590-600.

AbstractNMDA receptors (NMDARs) are key mediators of certain forms of synaptic plasticity and learning. NMDAR complexes are heteromers composed of an obligatory GluN1 subunit and one or more GluN2 (GluN2A-GluN2D) subunits. Different subunits confer distinct physiological and molecular properties to NMDARs, but their contribution to synaptic plasticity and learning in the adult brain remains uncertain. Here, we generated mice lacking GluN2B in pyramidal neurons of cortex and CA1 subregion of hippocampus. We found that hippocampal principal neurons of adult GluN2B mutants had faster decaying NMDAR-mediated EPSCs than nonmutant controls and were insensitive to GluN2B but not NMDAR antagonism. A subsaturating form of hippocampal long-term potentiation (LTP) was impaired in the mutants, whereas a saturating form of LTP was intact. An NMDAR-dependent form of long-term depression (LTD) produced by low-frequency stimulation combined with glutamate transporter inhibition was abolished in the mutants. Additionally, mutants exhibited decreased dendritic spine density in CA1 hippocampal neurons compared with controls. On multiple assays for corticohippocampal-mediated learning and memory (hidden platform Morris water maze, T-maze spontaneous alternation, and pavlovian trace fear conditioning), mutants were impaired. These data further demonstrate the importance of GluN2B for synaptic plasticity in the adult hippocampus and suggest a particularly critical role in LTD, at least the form studied here. The finding that loss of GluN2B was sufficient to cause learning deficits illustrates the contribution of GluN2B-mediated forms of plasticity to memory formation, with implications for elucidating NMDAR-related dysfunction in disease-related cognitive impairment.

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