Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Originally published in Science Express on 30 May 2002
Science 12 July 2002:
Vol. 297. no. 5579, pp. 211 - 218
DOI: 10.1126/science.1071795
Prev | Table of Contents | Next

Research Articles

Requirement for Hippocampal CA3 NMDA Receptors in Associative Memory Recall

Kazu Nakazawa,123 Michael C. Quirk,13* Raymond A. Chitwood,4 Masahiko Watanabe,5 Mark F. Yeckel,4dagger Linus D. Sun,13 Akira Kato,123ddagger Candice A. Carr,123 Daniel Johnston,4 Matthew A. Wilson,13 Susumu Tonegawa123§

Pattern completion, the ability to retrieve complete memories on the basis of incomplete sets of cues, is a crucial function of biological memory systems. The extensive recurrent connectivity of the CA3 area of hippocampus has led to suggestions that it might provide this function. We have tested this hypothesis by generating and analyzing a genetically engineered mouse strain in which the N-methyl-D-asparate (NMDA) receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall.

1 Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center,
2 Howard Hughes Medical Institute, and
3 Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4 Division of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
5 Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
*   Present address: Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA.

dagger    Present address: Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520-8001, USA.

ddagger    Present address: Shionogi Research Laboratories, Shionogi & Co., Ltd., Koka-gun, Shiga 520-3423, Japan.

§   To whom correspondence should be addressed. E-mail: tonegawa{at}mit.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine.
S. Rosi, V. Ramirez-Amaya, A. Vazdarjanova, E. E. Esparza, P. B. Larkin, J. R. Fike, G. L. Wenk, and C. A. Barnes (2009)
Brain
   Abstract »    Full Text »    PDF »
Pharmacological intervention of hippocampal CA3 NMDA receptors impairs acquisition and long-term memory retrieval of spatial pattern completion task.
L. Fellini, C. Florian, J. Courtey, and P. Roullet (2009)
Learn. Mem. 16, 387-394
   Abstract »    Full Text »    PDF »
Functional Specificity of Mossy Fiber Innervation of GABAergic Cells in the Hippocampus.
J. Szabadics and I. Soltesz (2009)
J. Neurosci. 29, 4239-4251
   Abstract »    Full Text »    PDF »
GLUT8, the enigmatic intracellular hexose transporter.
S. Schmidt, H.-G. Joost, and A. Schurmann (2009)
Am J Physiol Endocrinol Metab 296, E614-E618
   Abstract »    Full Text »    PDF »
Storage or retrieval deficit: The yin and yang of amnesia.
O. Hardt, S.-H. Wang, and K. Nader (2009)
Learn. Mem. 16, 224-230
   Abstract »    Full Text »    PDF »
From the Cover: Caloric restriction improves memory in elderly humans.
A. V. Witte, M. Fobker, R. Gellner, S. Knecht, and A. Floel (2009)
PNAS 106, 1255-1260
   Abstract »    Full Text »    PDF »
CNTRICS Final Task Selection: Long-Term Memory.
J. D. Ragland, R. Cools, M. Frank, D. A. Pizzagalli, A. Preston, C. Ranganath, and A. D. Wagner (2009)
Schizophr Bull 35, 197-212
   Abstract »    Full Text »    PDF »
Bidirectional Hebbian Plasticity at Hippocampal Mossy Fiber Synapses on CA3 Interneurons.
E. J. Galvan, E. Calixto, and G. Barrionuevo (2008)
J. Neurosci. 28, 14042-14055
   Abstract »    Full Text »    PDF »
Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration.
K. Tamai, M. Toyoshima, N. Tanaka, N. Yamamoto, Y. Owada, H. Kiyonari, K. Murata, Y. Ueno, M. Ono, T. Shimosegawa, et al. (2008)
Am. J. Pathol. 173, 1806-1817
   Abstract »    Full Text »    PDF »
Neuronal functions, feeding behavior, and energy balance in Slc2a3+/- mice.
S. Schmidt, M. Richter, D. Montag, T. Sartorius, V. Gawlik, A. M. Hennige, S. Scherneck, H. Himmelbauer, S. Z. Lutz, R. Augustin, et al. (2008)
Am J Physiol Endocrinol Metab 295, E1084-E1094
   Abstract »    Full Text »    PDF »
Lock-and-Key Mechanisms of Cerebellar Memory Recall Based on Rebound Currents.
D. Z. Wetmore, E. A. Mukamel, and M. J. Schnitzer (2008)
J Neurophysiol 100, 2328-2347
   Abstract »    Full Text »    PDF »
A Neural Coding Scheme Formed by the Combined Function of Gamma and Theta Oscillations.
J. Lisman and G. Buzsaki (2008)
Schizophr Bull 34, 974-980
   Abstract »    Full Text »    PDF »
Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?.
S. Daumas, J. Sandin, K. S. Chen, D. Kobayashi, J. Tulloch, S. J. Martin, D. Games, and R. G.M. Morris (2008)
Learn. Mem. 15, 625-632
   Abstract »    Full Text »    PDF »
Firing Rate Dynamics in the Hippocampus Induced by Trajectory Learning.
D. Ji and M. A. Wilson (2008)
J. Neurosci. 28, 4679-4689
   Abstract »    Full Text »    PDF »
Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear.
J. Ji and S. Maren (2008)
Learn. Mem. 15, 244-251
   Abstract »    Full Text »    PDF »
Transgenic Inhibition of Synaptic Transmission Reveals Role of CA3 Output in Hippocampal Learning.
T. Nakashiba, J. Z. Young, T. J. McHugh, D. L. Buhl, and S. Tonegawa (2008)
Science 319, 1260-1264
   Abstract »    Full Text »    PDF »
Modulation of CA3 Afferent Inputs by Novelty and Theta Rhythm.
D. M. Villarreal, A. L. Gross, and B. E. Derrick (2007)
J. Neurosci. 27, 13457-13467
   Abstract »    Full Text »    PDF »
The Medial Prefrontal Cortex Is Involved in Spatial Memory Retrieval under Partial-Cue Conditions.
Y. S. Jo, E. H. Park, I. H. Kim, S. K. Park, H. Kim, H. T. Kim, and J.-S. Choi (2007)
J. Neurosci. 27, 13567-13578
   Abstract »    Full Text »    PDF »
An attractor network in the hippocampus: Theory and neurophysiology.
E. T. Rolls (2007)
Learn. Mem. 14, 714-731
   Abstract »    Full Text »    PDF »
Pattern separation, pattern completion, and new neuronal codes within a continuous CA3 map.
S. Leutgeb and J. K. Leutgeb (2007)
Learn. Mem. 14, 745-757
   Abstract »    Full Text »    PDF »
Using immediate-early genes to map hippocampal subregional functions.
S. Kubik, T. Miyashita, and J. F. Guzowski (2007)
Learn. Mem. 14, 758-770
   Abstract »    Full Text »    PDF »
Behavioral functions of the CA3 subregion of the hippocampus.
R. P. Kesner (2007)
Learn. Mem. 14, 771-781
   Abstract »    Full Text »    PDF »
Memory retrieval time and memory capacity of the CA3 network: Role of gamma frequency oscillations.
L. de Almeida, M. Idiart, and J. E. Lisman (2007)
Learn. Mem. 14, 795-806
   Abstract »    Full Text »    PDF »
The relationship between the field-shifting phenomenon and representational coherence of place cells in CA1 and CA3 in a cue-altered environment.
I. Lee and J. J. Knierim (2007)
Learn. Mem. 14, 807-815
   Abstract »    Full Text »    PDF »
Gamma oscillations dynamically couple hippocampal CA3 and CA1 regions during memory task performance.
S. M. Montgomery and G. Buzsaki (2007)
PNAS 104, 14495-14500
   Abstract »    Full Text »    PDF »
Dentate Gyrus NMDA Receptors Mediate Rapid Pattern Separation in the Hippocampal Network.
T. J. McHugh, M. W. Jones, J. J. Quinn, N. Balthasar, R. Coppari, J. K. Elmquist, B. B. Lowell, M. S. Fanselow, M. A. Wilson, and S. Tonegawa (2007)
Science 317, 94-99
   Abstract »    Full Text »    PDF »
The Hippocampus and Spatial Memory: Findings with a Novel Modification of the Water Maze.
R. E. Clark, N. J. Broadbent, and L. R. Squire (2007)
J. Neurosci. 27, 6647-6654
   Abstract »    Full Text »    PDF »
Recruitment of an inhibitory hippocampal network after bursting in a single granule cell.
M. Mori, B. H. Gahwiler, and U. Gerber (2007)
PNAS 104, 7640-7645
   Abstract »    Full Text »    PDF »
Pattern Separation in the Dentate Gyrus and CA3 of the Hippocampus.
J. K. Leutgeb, S. Leutgeb, M.-B. Moser, and E. I. Moser (2007)
Science 315, 961-966
   Abstract »    Full Text »    PDF »
Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory.
K. Benchenane, H. Castel, M. Boulouard, R. Bluthe, M. Fernandez-Monreal, B. D. Roussel, J. P. Lopez-Atalaya, S. Butt-Gueulle, V. Agin, E. Maubert, et al. (2007)
J. Cell Sci. 120, 578-585
   Abstract »    Full Text »    PDF »
Knockdown of Nurr1 in the rat hippocampus: Implications to spatial discrimination learning and memory.
W. I. Colon-Cesario, M. M. Martinez-Montemayor, S. Morales, J. Felix, J. Cruz, M. Adorno, L. Pereira, N. Colon, C. S. Maldonado-Vlaar, and S. Pena de Ortiz (2006)
Learn. Mem. 13, 734-744
   Abstract »    Full Text »    PDF »
Permeant Ion Effects on External Mg2+ Block of NR1/2D NMDA Receptors..
A. Qian and J. W. Johnson (2006)
J. Neurosci. 26, 10899-10910
   Abstract »    Full Text »    PDF »
Fading in..
K. Nader and S.-H. Wang (2006)
Learn. Mem. 13, 530-535
   Abstract »    Full Text »    PDF »
Forebrain-Specific Glutamate Receptor B Deletion Impairs Spatial Memory But Not Hippocampal Field Long-Term Potentiation..
D. R. Shimshek, V. Jensen, T. Celikel, Y. Geng, B. Schupp, T. Bus, V. Mack, V. Marx, O. Hvalby, P. H. Seeburg, et al. (2006)
J. Neurosci. 26, 8428-8440
   Abstract »    Full Text »    PDF »
CREB antisense oligodeoxynucleotide administration into the dorsal hippocampal CA3 region impairs long- but not short-term spatial memory in mice.
C. Florian, N. Mons, and P. Roullet (2006)
Learn. Mem. 13, 465-472
   Abstract »    Full Text »    PDF »
Comparative plasticity of brain synapses in inbred mouse strains.
P. V. Nguyen (2006)
J. Exp. Biol. 209, 2293-2303
   Abstract »    Full Text »    PDF »
Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-D-aspartate Receptor.
S. L. Kaye, M. S. P. Sansom, and P. C. Biggin (2006)
J. Biol. Chem. 281, 12736-12742
   Abstract »    Full Text »    PDF »
Impaired Sequential Egocentric and Allocentric Memories in Forebrain-Specific-NMDA Receptor Knock-Out Mice during a New Task Dissociating Strategies of Navigation.
L. Rondi-Reig, G. H. Petit, C. Tobin, S. Tonegawa, J. Mariani, and A. Berthoz (2006)
J. Neurosci. 26, 4071-4081
   Abstract »    Full Text »    PDF »
Presynaptic and postsynaptic Ca2+ and CamKII contribute to long-term potentiation at synapses between individual CA3 neurons..
F.-M. Lu and R. D. Hawkins (2006)
PNAS 103, 4264-4269
   Abstract »    Full Text »    PDF »
Hippocampal CA3 NMDA Receptors Are Crucial for Adaptive Timing of Trace Eyeblink Conditioned Response.
Y. Kishimoto, K. Nakazawa, S. Tonegawa, Y. Kirino, and M. Kano (2006)
J. Neurosci. 26, 1562-1570
   Abstract »    Full Text »    PDF »
The Role of CA3 Hippocampal NMDA Receptors in Paired Associate Learning.
T. Rajji, D. Chapman, H. Eichenbaum, and R. Greene (2006)
J. Neurosci. 26, 908-915
   Abstract »    Full Text »    PDF »
{beta}1-Integrins Are Required for Hippocampal AMPA Receptor-Dependent Synaptic Transmission, Synaptic Plasticity, and Working Memory.
C.-S. Chan, E. J. Weeber, L. Zong, E. Fuchs, J. D. Sweatt, and R. L. Davis (2006)
J. Neurosci. 26, 223-232
   Abstract »    Full Text »    PDF »
Topography of Arc/Arg3.1 mRNA Expression in the Dorsal and Ventral Hippocampus Induced by Recent and Remote Spatial Memory Recall: Dissociation of CA3 and CA1 Activation.
P. A. Gusev, C. Cui, D. L. Alkon, and A. N. Gubin (2005)
J. Neurosci. 25, 9384-9397
   Abstract »    Full Text »    PDF »
{beta}1 Adrenergic Receptor-Mediated Enhancement of Hippocampal CA3 Network Activity.
C. W. D. Jurgens, K. E. Rau, C. A. Knudson, J. D. King, P. A. Carr, J. E. Porter, and V. A. Doze (2005)
J. Pharmacol. Exp. Ther. 314, 552-560
   Abstract »    Full Text »    PDF »
Age-Associated Alterations of Hippocampal Place Cells Are Subregion Specific.
I. A. Wilson, S. Ikonen, M. Gallagher, H. Eichenbaum, and H. Tanila (2005)
J. Neurosci. 25, 6877-6886
   Abstract »    Full Text »    PDF »
Encoding, consolidation, and retrieval of contextual memory: Differential involvement of dorsal CA3 and CA1 hippocampal subregions.
S. Daumas, H. Halley, B. Frances, and J.-M. Lassalle (2005)
Learn. Mem. 12, 375-382
   Abstract »    Full Text »    PDF »
Attractor Dynamics in the Hippocampal Representation of the Local Environment.
T. J. Wills, C. Lever, F. Cacucci, N. Burgess, and J. O'Keefe (2005)
Science 308, 873-876
   Abstract »    Full Text »    PDF »
Reduced Parahippocampal Connectivity Produces Schizophrenia-like Memory Deficits in Simulated Neural Circuits With Reduced Parahippocampal Connectivity.
L. M. Talamini, M. Meeter, B. Elvevag, J. M. J. Murre, and T. E. Goldberg (2005)
Arch Gen Psychiatry 62, 485-493
   Abstract »    Full Text »    PDF »
Size Does Matter: Generation of Intrinsic Network Rhythms in Thick Mouse Hippocampal Slices.
C. Wu, W. P. Luk, J. Gillis, F. Skinner, and L. Zhang (2005)
J Neurophysiol 93, 2302-2317
   Abstract »    Full Text »    PDF »
NR2 subunit-dependence of NMDA receptor channel block by external Mg2+.
A. Qian, A. L. Buller, and J. W. Johnson (2005)
J. Physiol. 562, 319-331
   Abstract »    Full Text »    PDF »
Regulation of Brain Proteolytic Activity Is Necessary for the In Vivo Function of NMDA Receptors.
M. Kvajo, H. Albrecht, M. Meins, U. Hengst, E. Troncoso, S. Lefort, J. Z. Kiss, C. C. H. Petersen, and D. Monard (2004)
J. Neurosci. 24, 9734-9743
   Abstract »    Full Text »    PDF »
Cognitive Memory: Cellular and Network Machineries and Their Top-Down Control.
Y. Miyashita (2004)
Science 306, 435-440
   Abstract »    Full Text »    PDF »
Spatial Representation in the Entorhinal Cortex.
M. Fyhn, S. Molden, M. P. Witter, E. I. Moser, and M.-B. Moser (2004)
Science 305, 1258-1264
   Abstract »    Full Text »    PDF »
Distinct Ensemble Codes in Hippocampal Areas CA3 and CA1.
S. Leutgeb, J. K. Leutgeb, A. Treves, M.-B. Moser, and E. I. Moser (2004)
Science 305, 1295-1298
   Abstract »    Full Text »    PDF »
Molecular Biology and Ontogeny of Glutamate Receptors in the Mammalian Central Nervous System.
T. A. Simeone, R. M. Sanchez, and J. M. Rho (2004)
J Child Neurol 19, 343-360
   Abstract »    PDF »
Coincidence detection enhances appropriate wiring of the nervous system.
N. C. Spitzer (2004)
PNAS 101, 5311-5312
   Full Text »    PDF »
Cholinergic Activity Enhances Hippocampal Long-Term Potentiation in CA1 during Walking in Rats.
L. S. Leung, B. Shen, N. Rajakumar, and J. Ma (2003)
J. Neurosci. 23, 9297-9304
   Abstract »    Full Text »    PDF »
{alpha}1E-Containing Ca2+ channels are involved in synaptic plasticity.
J. Breustedt, K. E. Vogt, R. J. Miller, R. A. Nicoll, and D. Schmitz (2003)
PNAS 100, 12450-12455
   Abstract »    Full Text »    PDF »
Improvement in Fear Memory by Histamine-Elicited ERK2 Activation in Hippocampal CA3 Cells.
M. G. Giovannini, M. Efoudebe, M. B. Passani, E. Baldi, C. Bucherelli, F. Giachi, R. Corradetti, and P. Blandina (2003)
J. Neurosci. 23, 9016-9023
   Abstract »    Full Text »    PDF »
Brain Region-Specific Mechanisms for Acute Morphine-Induced Mitogen-Activated Protein Kinase Modulation and Distinct Patterns of Activation during Analgesic Tolerance and Locomotor Sensitization.
S. Eitan, C. D. Bryant, N. Saliminejad, Y. C. Yang, E. Vojdani, D. Keith Jr, R. Polakiewicz, and C. J. Evans (2003)
J. Neurosci. 23, 8360-8369
   Abstract »    Full Text »    PDF »
Cognitive Strategy-Specific Increases in Phosphorylated cAMP Response Element-Binding Protein and c-Fos in the Hippocampus and Dorsal Striatum.
P. J. Colombo, J. J. Brightwell, and R. A. Countryman (2003)
J. Neurosci. 23, 3547-3554
   Abstract »    Full Text »    PDF »
Essential function of alpha -calcium/calmodulin-dependent protein kinase II in neurotransmitter release at a glutamatergic central synapse.
H. L. Hinds, I. Goussakov, K. Nakazawa, S. Tonegawa, and V. Y. Bolshakov (2003)
PNAS 100, 4275-4280
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)