title: Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning.
abstract: NMDA 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.
authors.affiliation: 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
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Brigman
authors.forename: Tara
authors.initials: T
authors.lastname: Wright
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Talani
authors.forename: Shweta
authors.initials: S
authors.lastname: Prasad-Mulcare
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Jinde
authors.forename: Gail K
authors.initials: GK
authors.lastname: Seabold
authors.forename: Poonam
authors.initials: P
authors.lastname: Mathur
authors.forename: Margaret I
authors.initials: MI
authors.lastname: Davis
authors.forename: Roland
authors.initials: R
authors.lastname: Bock
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gustin
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Alvarez
authors.forename: Kazu
authors.initials: K
authors.lastname: Nakazawa
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology* / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D049229:Dendritic Spines / Q000648:ultrastructure*; D019706:Excitatory Postsynaptic Potentials; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D018782:Maze Learning; D051379:Mice; D008817:Mice, Mutant Strains; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate