title: Hippocampal long-term depression is required for the consolidation of spatial memory.
abstract: Although NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are candidate mechanisms for long-term spatial memory, the precise contributions of LTP and LTD remain poorly understood. Here, we report that LTP and LTD in the hippocampal CA1 region of freely moving adult rats were prevented by NMDAR 2A (GluN2A) and 2B subunit (GluN2B) preferential antagonists, respectively. These results strongly suggest that NMDAR subtype preferential antagonists are appropriate tools to probe the roles of LTP and LTD in spatial memory. Using a Morris water maze task, the LTP-blocking GluN2A antagonist had no significant effect on any aspect of performance, whereas the LTD-blocking GluN2B antagonist impaired spatial memory consolidation. Moreover, similar spatial memory deficits were induced by inhibiting the expression of LTD with intrahippocampal infusion of a short peptide that specifically interferes with AMPA receptor endocytosis. Taken together, our findings support a functional requirement of hippocampal CA1 LTD in the consolidation of long-term spatial memory.
authors.affiliation: Brain Research Centre, University of British Columbia, BC, Canada V6T 2B5.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ge
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Dong
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Bagot
authors.forename: John G
authors.initials: JG
authors.lastname: Howland
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
authors.forename: Tak Pan
authors.initials: TP
authors.lastname: Wong
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D010636:Phenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D021122:Protein Subunits; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000145:classification; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010879:Piperazines; D010880:Piperidines; D021122:Protein Subunits; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
references.citation: J Neurosci. 2007 Dec 12;27(50):13649-54
references.pmid: 18077676
references.citation: Neuron. 2006 Apr 6;50(1):127-43
references.pmid: 16600861
references.citation: Behav Pharmacol. 1992 Aug;3(4):415-421
references.pmid: 11224144
references.citation: EMBO J. 2004 Mar 10;23(5):1040-50
references.pmid: 14976558
references.citation: Science. 2005 Apr 1;308(5718):83-8
references.pmid: 15746389
references.citation: J Pharmacol Exp Ther. 1997 Dec;283(3):1285-92
references.pmid: 9400004
references.citation: Cell. 1996 Dec 27;87(7):1327-38
references.pmid: 8980238
references.citation: Science. 1999 Jun 11;284(5421):1805-11
references.pmid: 10364547
references.citation: Annu Rev Neurosci. 2000;23:649-711
references.pmid: 10845078
references.citation: J Neurosci. 2005 Sep 14;25(37):8386-90
references.pmid: 16162920
references.citation: Neuron. 1996 Feb;16(2):333-44
references.pmid: 8789948
references.citation: Eur J Pharmacol. 2003 Aug 29;476(3):193-9
references.pmid: 12969766
references.citation: Neuropharmacology. 2003 Mar;44(3):324-41
references.pmid: 12604092
references.citation: Science. 2004 May 14;304(5673):1021-4
references.pmid: 15143284
references.citation: Cell. 1997 Mar 7;88(5):615-26
references.pmid: 9054501
references.citation: J Neurosci. 2003 Nov 26;23(34):10791-9
references.pmid: 14645471
references.citation: Nature. 1998 Aug 27;394(6696):891-4
references.pmid: 9732871
references.citation: Cell. 1996 Dec 27;87(7):1339-49
references.pmid: 8980239
references.citation: Science. 2006 Aug 25;313(5790):1093-7
references.pmid: 16931756
references.citation: Nat Neurosci. 2005 Aug;8(8):1069-77
references.pmid: 16025106
references.citation: J Neurosci. 2008 Apr 2;28(14):3623-30
references.pmid: 18385321
references.citation: J Neurosci. 2005 Jul 20;25(29):6907-10
references.pmid: 16033900
references.citation: Bioorg Med Chem Lett. 2002 Apr 8;12(7):1099-102
references.pmid: 11909726
references.citation: Proc Natl Acad Sci U S A. 2004 May 25;101(21):8192-7
references.pmid: 15150407
references.citation: Nat Neurosci. 2002 Sep;5(9):868-73
references.pmid: 12195431
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: Hippocampus. 2006;16(11):907-15
references.pmid: 17024679
references.citation: Nature. 1998 Aug 20;394(6695):787-90
references.pmid: 9723618
references.citation: Nature. 1982 Jun 24;297(5868):681-3
references.pmid: 7088155
references.citation: Cell. 2001 Nov 30;107(5):617-29
references.pmid: 11733061
references.citation: Neuropharmacology. 2007 Jan;52(1):71-6
references.pmid: 16899258
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8739-44
references.pmid: 10411945
references.citation: J Neurosci. 2010 Mar 31;30(13):4590-600
references.pmid: 20357110
references.citation: J Neurosci. 2006 Feb 1;26(5):1331-3
references.pmid: 16452656
references.citation: Neuron. 2008 Apr 10;58(1):104-17
references.pmid: 18400167
references.citation: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4363-7
references.pmid: 1350090
references.citation: Nat Rev Neurosci. 2010 Jul;11(7):459-73
references.pmid: 20559335
references.citation: Nature. 1995 Jan 12;373(6510):151-5
references.pmid: 7816096
references.citation: Psychol Rev. 1992 Apr;99(2):195-231
references.pmid: 1594723
references.citation: Neurobiol Learn Mem. 2010 Feb;93(2):261-7
references.pmid: 19857581
references.citation: Hippocampus. 1996;6(1):43-51
references.pmid: 8878741
references.citation: Nature. 1986 Feb 27-Mar 5;319(6056):774-6
references.pmid: 2869411
references.citation: Neuropharmacology. 2007 Jan;52(1):60-70
references.pmid: 16904707
references.citation: J Physiol. 1983 Jan;334:33-46
references.pmid: 6306230
references.citation: PLoS One. 2008 Aug 06;3(8):e2848
references.pmid: 18682723
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11471-6
references.pmid: 17592137