CoChat
Sign Up
Cited by 339Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsTreatment of Major Depression

Loss of GluN2B-Containing NMDA Receptors in CA1 Hippocampus and Cortex Impairs Long-Term Depression, Reduces Dendritic Spine Density, and Disrupts Learning

Open access
Brigman, Jonathan L., Wright, Tara, Talani, Giuseppe, Prasad-Mulcare, Shweta, Jinde, Seiichiro, Seabold, Gail K., Mathur, Poonam, Davis, Margaret I. +8 more·2010·The Journal of Neuroscience
DOI 10.1523/jneurosci.0640-10.2010PMC PMC2869199
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1523/jneurosci.0640-10.2010

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Removal of the GluN2B subunit by knockout or knockdown produces variable effects on LTP, ranging from complete block to partial impairment.

    “The first approach removed the GluN2B subunit, either by knockout or knockdown. The results vary from a complete block of LTP (226, 227) to a partial impairment (228, 229).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [229]

  • Several genes involved in synaptic plasticity, synaptic transmission, and long-term potentiation (Gria1, Grin2b, Wasf1) showed low expression in WT, ApoeCh, and PS19, but were upregulated in PS19;ApoeCh.

    “There were also several genes (i.e., Gria1, Grin2b, Wasf1), involved in synaptic plasticity, synaptic transmission, and long-term potentiation that showed low expression in WT, ApoeCh, and PS19, but which were upregulated in PS19;ApoeCh (Fig. 8c) [70–73].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [72]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 61 · Cited by 339

Research works printed but not linked: 56

  1. Akashi K Kakizaki T Kamiya H Fukaya M Yamasaki M Abe M Natsume R Watanabe M Sakimura K NMDA receptor GluN2B (GluRepsilon2/NR2B) subunit is crucial for channel function, postsynaptic macromolecular organization, and actin cytoskeleton at hippocampal CA3 synapses J Neurosci 2009 29 10869 10882 19726645 PMC6665524
  2. Alvarez VA Sabatini BL Anatomical and physiological plasticity of dendritic spines Annu Rev Neurosci 2007 30 79 97 17280523
  3. Bannerman DM Rawlins JN Good MA The drugs don’t work-or do they? Pharmacological and transgenic studies of the contribution of NMDA and GluR-A-containing AMPA receptors to hippocampal-dependent memory Psychopharmacology (Berl) 2006 188 552 566 16676163
  4. Bannerman DM Niewoehner B Lyon L Romberg C Schmitt WB Taylor A Sanderson DJ Cottam J Sprengel R Seeburg PH Kohr G Rawlins JN NMDA Receptor Subunit NR2A Is Required for Rapidly Acquired Spatial Working Memory But Not Incremental Spatial Reference Memory J Neurosci 2008 28 3623 3630 18385321 PMC6671075
  5. Barria A Malinow R NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII Neuron 2005 48 289 301 16242409
  6. Berberich S Jensen V Hvalby O Seeburg PH Kohr G The role of NMDAR subtypes and charge transfer during hippocampal LTP induction Neuropharmacology 2007 52 77 86 16901514
  7. Berberich S Punnakkal P Jensen V Pawlak V Seeburg PH Hvalby O Kohr G Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation J Neurosci 2005 25 6907 6910 16033900 PMC6725356
  8. Boyce-Rustay JM Holmes A Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice Neuropsychopharmacology 2006 31 2405 2414 16482087
  9. Brigman JL Feyder M Saksida LM Bussey TJ Mishina M Holmes A Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit Learn Mem 2008 15 50 54 18230672 PMC3575092
  10. Brown AM Deutch AY Colbran RJ Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism Eur J Neurosci 2005 22 247 256 16029214 PMC4819997
  11. Chazot PL Lawrence S Thompson CL Studies on the subtype selectivity of CP-101,606: evidence for two classes of NR2B-selective NMDA receptor antagonists Neuropharmacology 2002 42 319 324 11897110
  12. Clayton DA Mesches MH Alvarez E Bickford PC Browning MD A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat J Neurosci 2002 22 3628 3637 11978838 PMC6758397
  13. Cull-Candy S Brickley S Farrant M NMDA receptor subunits: diversity, development and disease Curr Opin Neurobiol 2001 11 327 335 11399431
  14. Duffy S Labrie V Roder JC D-Serine Augments NMDA-NR2B Receptor-Dependent Hippocampal Long-Term Depression and Spatial Reversal Learning Neuropsychopharmacology 2008 33 1004 1018 17625504
  15. Feyder M Wiedholz L Sprengel R Holmes A Impaired Associative Fear Learning in Mice with Complete Loss or Haploinsufficiency of AMPA GluR1 Receptors Front Behav Neurosci 2007 1 4 18958186 PMC2525858
  16. Fonseca R Nagerl UV Bonhoeffer T Neuronal activity determines the protein synthesis dependence of long-term potentiation Nat Neurosci 2006 9 478 480 16531998
  17. Fox CJ Russell KI Wang YT Christie BR Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo Hippocampus 2006 16 907 915 17024679
  18. Gardoni F Mauceri D Malinverno M Polli F Costa C Tozzi A Siliquini S Picconi B Cattabeni F Calabresi P Di Luca M Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not long-term depression J Neurosci 2009 29 669 677 19158293 PMC6665154
  19. Grutzendler J Tsai J Gan WB Rapid labeling of neuronal populations by ballistic delivery of fluorescent dyes Methods 2003 30 79 85 12695105
  20. Hawasli AH Benavides DR Nguyen C Kansy JW Hayashi K Chambon P Greengard P Powell CM Cooper DC Bibb JA Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation Nat Neurosci 2007 10 880 886 17529984 PMC3910113
  21. Hestrin S Developmental regulation of NMDA receptor-mediated synaptic currents at a central synapse Nature 1992 357 686 689 1377360
  22. Holmes A Wrenn CC Harris AP Thayer KE Crawley JN Behavioral profiles of inbred strains on novel olfactory, spatial and emotional tests for reference memory in mice Genes Brain Behav 2002 1 55 69 12886950
  23. Huerta PT Sun LD Wilson MA Tonegawa S Formation of temporal memory requires NMDA receptors within CA1 pyramidal neurons Neuron 2000 25 473 480 10719900
  24. Huh KH Wenthold RJ Turnover analysis of glutamate receptors identifies a rapidly degraded pool of the N-methyl-D-aspartate receptor subunit, NR1, in cultured cerebellar granule cells J Biol Chem 1999 274 151 157 9867823
  25. Iwasato T Erzurumlu RS Huerta PT Chen DF Sasaoka T Ulupinar E Tonegawa S NMDA receptor-dependent refinement of somatotopic maps Neuron 1997 19 1201 1210 9427244
  26. Kesner RP Rogers J An analysis of independence and interactions of brain substrates that subserve multiple attributes, memory systems, and underlying processes Neurobiol Learn Mem 2004 82 199 215 15464404
  27. Kim JJ Clark RE Thompson RF Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses Behav Neurosci 1995 109 195 203 7619310
  28. Kirkwood A Rioult MC Bear MF Experience-dependent modification of synaptic plasticity in visual cortex Nature 1996 381 526 528 8632826
  29. Kirov SA Harris KM Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated Nat Neurosci 1999 2 878 883 10491607
  30. Kiyama Y Manabe T Sakimura K Kawakami F Mori H Mishina M Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilon1 subunit J Neurosci 1998 18 6704 6712 9712642 PMC6792962
  31. Kohr G Jensen V Koester HJ Mihaljevic AL Utvik JK Kvello A Ottersen OP Seeburg PH Sprengel R Hvalby O Intracellular domains of NMDA receptor subtypes are determinants for long-term potentiation induction J Neurosci 2003 23 10791 10799 14645471 PMC6740988
  32. Kutsuwada T Sakimura K Manabe T Takayama C Katakura N Kushiya E Natsume R Watanabe M Inoue Y Yagi T Aizawa S Arakawa M Takahashi T Nakamura Y Mori H Mishina M Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice Neuron 1996 16 333 344 8789948
  33. Laemmli UK Cleavage of structural proteins during the assembly of the head of bacteriophage T4 Nature 1970 227 680 685 5432063
  34. Lee KW Kim Y Kim AM Helmin K Nairn AC Greengard P Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens Proc Natl Acad Sci U S A 2006 103 3399 3404 16492766 PMC1413917
  35. Liu L Wong TP Pozza MF Lingenhoehl K Wang Y Sheng M Auberson YP Wang YT Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity Science 2004 304 1021 1024 15143284
  36. Malenka RC Bear MF LTP and LTD: an embarrassment of riches Neuron 2004 44 5 21 15450156
  37. Massey PV Johnson BE Moult PR Auberson YP Brown MW Molnar E Collingridge GL Bashir ZI Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression J Neurosci 2004 24 7821 7828 15356193 PMC6729941
  38. Morishita W Lu W Smith GB Nicoll RA Bear MF Malenka RC Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression Neuropharmacology 2007 52 71 76 16899258
  39. Morris RG Davis S Butcher SP Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Philos Trans R Soc Lond B Biol Sci 1990 329 187 204 1978364
  40. Nakazawa K McHugh TJ Wilson MA Tonegawa S NMDA receptors, place cells and hippocampal spatial memory Nat Rev Neurosci 2004 5 361 372 15100719
  41. Nakazawa T Komai S Watabe AM Kiyama Y Fukaya M Arima-Yoshida F Horai R Sudo K Ebine K Delawary M Goto J Umemori H Tezuka T Iwakura Y Watanabe M Yamamoto T Manabe T NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity Embo J 2006 25 2867 2877 16710293 PMC1500840
  42. Neyton J Paoletti P Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach J Neurosci 2006 26 1331 1333 16452656 PMC6675501
  43. Quinlan EM Lebel D Brosh I Barkai E A molecular mechanism for stabilization of learning-induced synaptic modifications Neuron 2004 41 185 192 14741100
  44. Quinn JJ Loya F Ma QD Fanselow MS Dorsal hippocampus NMDA receptors differentially mediate trace and contextual fear conditioning Hippocampus 2005 15 665 674 15959918
  45. Rosenmund C Stern-Bach Y Stevens CF The tetrameric structure of a glutamate receptor channel Science 1998 280 1596 1599 9616121
  46. Sessoms-Sikes S Honse Y Lovinger DM Colbran RJ CaMKIIalpha enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism Mol Cell Neurosci 2005 29 139 147 15866054
  47. Shen W Flajolet M Greengard P Surmeier DJ Dichotomous dopaminergic control of striatal synaptic plasticity Science 2008 321 848 851 18687967 PMC2833421
  48. Silverstein AM Barrow CA Davis AJ Mumby MC Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits Proc Natl Acad Sci U S A 2002 99 4221 4226 11904383 PMC123629
  49. Steiner P Higley MJ Xu W Czervionke BL Malenka RC Sabatini BL Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity Neuron 2008 60 788 802 19081375 PMC2671083
  50. Takehara K Kawahara S Munemoto Y Kuriyama H Mori H Mishina M Kirino Y The N-methyl-D-aspartate (NMDA)-type glutamate receptor GluRepsilon2 is important for delay and trace eyeblink conditioning in mice Neurosci Lett 2004 364 43 47 15193753
  51. Tang YP Shimizu E Dube GR Rampon C Kerchner GA Zhuo M Liu G Tsien JZ Genetic enhancement of learning and memory in mice Nature 1999 401 63 69 10485705
  52. Towbin H Staehelin T Gordon J Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications Proc Natl Acad Sci U S A 1979 76 4350 4354 388439 PMC411572
  53. Tsien JZ Chen DF Gerber D Tom C Mercer EH Anderson DJ Mayford M Kandel ER Tonegawa S Subregion- and cell type-restricted gene knockout in mouse brain Cell 1996b 87 1317 1326 8980237
  54. von Engelhardt J Doganci B Jensen V Hvalby O Gongrich C Taylor A Barkus C Sanderson DJ Rawlins JN Seeburg PH Bannerman DM Monyer H Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks Neuron 2008 60 846 860 19081379
  55. Yang RJ Mozhui K Karlsson RM Cameron HA Williams RW Holmes A Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning Neuropsychopharmacology 2008 33 2595 2604 18185497
  56. Zhao MG Toyoda H Lee YS Wu LJ Ko SW Zhang XH Jia Y Shum F Xu H Li BM Kaang BK Zhuo M Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory Neuron 2005 47 859 872 16157280

Authors
Brigman, J. L., Wright, T., Talani, G., Prasad-Mulcare, S., Jinde, S., Seabold, G. K., Mathur, P., Davis, M. I., Bock, R., Gustin, R. M., Colbran, R. J., Alvarez, V. A., Nakazawa, K., Delpire, E., Lovinger, D. M., & Holmes, A.
Affiliations
  • National Institutes of Health (US)
  • National Institute on Alcohol Abuse and Alcoholism (US)
  • Vanderbilt University Medical Center (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2010-03-31
Volume
30
Issue
13
Pages
4590-4600
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.0640-10.2010
PMC
PMC2869199
OpenAlex
W2070475355
Cited by
339
References
61
Citations by year
2026: 9 · 2025: 12 · 2024: 17 · 2023: 14 · 2022: 21 · 2021: 21 · 2020: 20 · 2019: 24 · 2018: 28 · 2017: 17 · 2016: 25 · 2015: 20 · 2014: 31 · 2013: 27 · 2012: 29
FWCI
10.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
Funders
  • National Institutes of Health (1f31ns061537-01a2, NIH0012772814)
  • National Institute on Alcohol Abuse and Alcoholism (U01AA013514, AA013514, ZIAAA000411, ZIAAA000421)
  • National Institute of Mental Health (MH063232, R01MH063232)
  • National Institute of Neurological Disorders and Stroke (F31-NS061537)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
GluN2B, NMDA receptor, long-term depression, long-term potentiation, synaptic plasticity, dendritic spine density, hippocampal CA1, cortical pyramidal neurons, learning and memory, low-frequency stimulation, cognitive impairment
MeSH terms
Animals, Cerebral Cortex, Mice, Mutant Strains, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Patch-Clamp Techniques, Maze Learning, Excitatory Postsynaptic Potentials, Long-Term Synaptic Depression, Dendritic Spines, Mice, CA1 Region, Hippocampal

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review