Recent studies using transgenic mice lacking NMDA receptors in the hippocampus challenge the long-standing hypothesis that hippocampal long-term potentiation-like mechanisms underlie the encoding and storage of associative long-term spatial memories. However, it may not be the synaptic plasticity-dependent memory hypothesis that is wrong; instead, it may be the role of the hippocampus that needs to be re-examined. We present an account of hippocampal function that explains its role in both memory and anxiety.
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O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Oxford Univ. Press, 1978).
Burgess, N., Maguire, E. A. & O'Keefe, J. The human hippocampus and spatial and episodic memory. Neuron 35, 625–641 (2002).
Olton, D. S. & Samuelson, R. J. Remembrance of places passed — spatial memory in rats. J. Exp. Psychol. Anim. Behav. Process. 2, 97–116 (1976).
Morris, R. G., Garrud, P., Rawlins, J. N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).
Morris, R. G., Schenk, F., Tweedie, F. & Jarrard, L. E. Ibotenate lesions of hippocampus and/or subiculum: dissociating components of allocentric spatial learning. Eur. J. Neurosci. 2, 1016–1028 (1990).
Rawlins, J. N. & Olton, D. S. The septo-hippocampal system and cognitive mapping. Behav. Brain Res. 5, 331–358 (1982).
O'Keefe, J. & Dostrovsky, J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171–175 (1971).
Maguire, E. A. et al. Knowing where and getting there: a human navigation network. Science 280, 921–924 (1998).
Maguire, E. A., Burgess, N. & O'Keefe, J. Human spatial navigation: cognitive maps, sexual dimorphism, and neural substrates. Curr. Opin. Neurobiol. 9, 171–177 (1999).
Sanderson, D. J. et al. Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model. Learn. Mem. 16, 379–386 (2009).
Sanderson, D. J. & Bannerman, D. M. The role of habituation in hippocampus-dependent spatial working memory tasks: evidence from GluA1 AMPA receptor subunit knockout mice. Hippocampus 22, 981–994 (2012).
Fyhn, M., Molden, S., Witter, M. P., Moser, E. I. & Moser, M. B. Spatial representation in the entorhinal cortex. Science 305, 1258–1264 (2004).
Hafting, T., Fyhn, M., Molden, S., Moser, M. B. & Moser, E. I. Microstructure of a spatial map in the entorhinal cortex. Nature 436, 801–806 (2005).
Taube, J. S., Muller, R. U. & Ranck, J. B. Jr. Head-direction cells recorded from the postsubiculum in freely moving rats. II. Effects of environmental manipulations. J. Neurosci. 10, 436–447 (1990).
Taube, J. S., Muller, R. U. & Ranck, J. B. Jr. Head-direction cells recorded from the postsubiculum in freely moving rats. I. Description and quantitative analysis. J. Neurosci. 10, 420–435 (1990).
Savelli, F., Yoganarasimha, D. & Knierim, J. J. Influence of boundary removal on the spatial representations of the medial entorhinal cortex. Hippocampus 18, 1270–1282 (2008).
Solstad, T., Boccara, C. N., Kropff, E., Moser, M. B. & Moser, E. I. Representation of geometric borders in the entorhinal cortex. Science 322, 1865–1868 (2008).
Lever, C., Burton, S., Jeewajee, A., O'Keefe, J. & Burgess, N. Boundary vector cells in the subiculum of the hippocampal formation. J. Neurosci. 29, 9771–9777 (2009).
Eichenbaum, H., Stewart, C. & Morris, R. G. Hippocampal representation in place learning. J. Neurosci. 10, 3531–3542 (1990).
Schmitt, W. B., Deacon, R. M., Seeburg, P. H., Rawlins, J. N. & Bannerman, D. M. A within-subjects, within-task demonstration of intact spatial reference memory and impaired spatial working memory in glutamate receptor-A-deficient mice. J. Neurosci. 23, 3953–3959 (2003).
Hebb, D. O. The Organization of Behavior (John Wiley & Sons, 1949).
Hebb, D. O. Textbook of Psychology 3rd edn (W. B. Saunders Company, 1972).
Konorski, J. Conditioned Reflexes and Neuron Organization (Hefner, 1948).
Bliss, T. V. & Lømo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356 (1973).
Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).
Keith, J. R. & Rudy, J. W. Why NMDA receptor-dependent long-term potentiation may not be a mechanism of learning and memory: re-appraisal of the NMDA receptor blockade strategy. Psychobiology 18, 251–257 (1990).
Gallistel, C. R. & Matzel, L. D. The neuroscience of learning: beyond the hebbian synapse. Annu. Rev. Psychol. 64, 169–200 (2013).
Shors, T. J. & Matzel, L. D. Long-term potentiation: what's learning got to do with it? Behav. Brain Sci. 20, 597–614 (1997).
Bannerman, D. M., Rawlins, J. N. P. & Good, M. A. 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.) 188, 552–566 (2006).
Cain, D. P., Saucier, D., Hall, J., Hargreaves, E. L. & Boon, F. Detailed behavioral analysis of water maze acquisition under APV or CNQX: contribution of sensorimotor disturbances to drug-induced acquisition deficits. Behav. Neurosci. 110, 86–102 (1996).
Saucier, D. & Cain, D. P. Spatial learning without NMDA receptor-dependent long-term potentiation. Nature 378, 186–189 (1995).
Bannerman, D. M. et al. Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion. Nature Neurosci. 15, 1153–1159 (2012).
Collingridge, G. L., Kehl, S. J. & McLennan, H. Excitatory amino acids in synaptic transmission in the Schaffer collateral–commissural pathway of the rat hippocampus. J. Physiol. 334, 33–46 (1983).
Morris, R. G., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).
Morris, R. G. Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J. Neurosci. 9, 3040–3057 (1989).
Davis, S., Butcher, S. P. & Morris, R. G. The NMDA receptor antagonist D-2-amino-5- phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J. Neurosci. 12, 21–34 (1992).
Bannerman, D. M., Good, M. A., Butcher, S. P., Ramsay, M. & Morris, R. G. Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature 378, 182–186 (1995).
Laube, B., Kuhse, J. & Betz, H. Evidence for a tetrameric structure of recombinant NMDA receptors. J. Neurosci. 18, 2954–2961 (1998).
Seeburg, P. H. The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 16, 359–365 (1993).
Sakimura, K. et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit. Nature 373, 151–155 (1995).
Kiyama, Y. et al. Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor ε1 subunit. J. Neurosci. 18, 6704–6712 (1998).
Bannerman, D. M. et al. NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory. J. Neurosci. 28, 3623–3630 (2008).
Tsien, J. Z. et al. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87, 1317–1326 (1996).
Tsien, J. Z., Huerta, P. T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996).
Wiltgen, B. J. et al. A role for calcium-permeable AMPA receptors in synaptic plasticity and learning. PLoS ONE 5, e12818 (2010).
Hoeffer, C. A. et al. Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60, 832–845 (2008).
Fukaya, M., Kato, A., Lovett, C., Tonegawa, S. & Watanabe, M. Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Proc. Natl Acad. Sci. USA 100, 4855–4860 (2003).
Brigman, J. L. et al. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J. Neurosci. 30, 4590–4600 (2010).
Rondi-Reig, L. et al. Impaired sequential egocentric and allocentric memories in forebrain-specific-NMDA receptor knock-out mice during a new task dissociating strategies of navigation. J. Neurosci. 26, 4071–4081 (2006).
Niewoehner, B. et al. Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus. Eur. J. Neurosci. 25, 837–846 (2007).
Taylor, A. M. B. et al. Hippocampal NMDARs are important for behavioural inhibition but not for encoding associative spatial memories. Phil. Trans. R. Soc. B 369, 20130149 (2014).
Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).
Maren, S., Phan, K. L. & Liberzon, I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nature Rev. Neurosci. 14, 417–428 (2013).
Tsetsenis, T., Ma, X. H., Lo Iacono, L., Beck, S. G. & Gross, C. Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nature Neurosci. 10, 896–902 (2007).
Marr, D. Simple memory: a theory for archicortex. Phil. Trans. R. Soc. Lond. B 262, 23–81 (1971).
Rolls, E. T. A theory of hippocampal function in memory. Hippocampus 6, 601–620 (1996).
O'Reilly, R. C. & McClelland, J. L. Hippocampal conjunctive encoding, storage, and recall: avoiding a trade-off. Hippocampus 4, 661–682 (1994).
McNaughton, B. L. in Neural Connection, Mental Computation (eds Nadel, L., Cooper, L. A., & Culicover, P.) 285–350 (MIT Press, 1989).
Rolls, E. T. & Treves, A. Neural Networks and Brain Function (Oxford Univ. Press, 1998).
Shapiro, M. L. & Olton, D. S. in Memory Systems (eds Schacter, D. L. & Tulving, E.) 141–146 (MIT Press, 1994).
Gilbert, P. E., Kesner, R. P. & Lee, I. Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1. Hippocampus 11, 626–636 (2001).
McHugh, T. J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–99 (2007).
Clelland, C. D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).
Groves, J. O. L. et al. Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic rat model. PLoS Genet. 9, e1003718 (2013).
Morris, R. G., Davis, S. & Butcher, S. P. Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Phil. Trans. R. Soc. Lond. B 329, 187–204 (1990).
von Engelhardt, J. et al. Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron 60, 846–860 (2008).
Steele, R. J. & Morris, R. G. Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5. Hippocampus 9, 118–136 (1999).
Nakazawa, K. et al. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38, 305–315 (2003).
Nakazawa, K. et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 297, 211–218 (2002).
Grover, L. M. & Teyler, T. J. N-methyl-D-aspartate receptor-independent long-term potentiation in area CA1 of rat hippocampus: input-specific induction and preclusion in a non-tetanized pathway. Neuroscience 49, 7–11 (1992).
Silva, A. J. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J. Neurobiol. 54, 224–237 (2003).
Steffenach, H. A., Witter, M., Moser, M. B. & Moser, E. I. Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex. Neuron 45, 301–313 (2005).
Mariano, T. Y. et al. Impulsive choice in hippocampal but not orbitofrontal cortex-lesioned rats on a nonspatial decision-making maze task. Eur. J. Neurosci. 30, 472–484 (2009).
Bannerman, D. M. et al. Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions. Behav. Neurosci. 113, 1170–1188 (1999).
Fortin, N. J., Agster, K. L. & Eichenbaum, H. B. Critical role of the hippocampus in memory for sequences of events. Nature Neurosci. 5, 458–462 (2002).
Kesner, R. P., Gilbert, P. E. & Barua, L. A. The role of the hippocampus in memory for the temporal order of a sequence of odors. Behav. Neurosci. 116, 286–290 (2002).
Marshall, V. J., McGregor, A., Good, M. & Honey, R. C. Hippocampal lesions modulate both associative and nonassociative priming. Behav. Neurosci. 118, 377–382 (2004).
Honey, R. C. & Good, M. Associative modulation of the orienting response: distinct effects revealed by hippocampal lesions. J. Exp. Psychol. Anim. Behav. Process 26, 3–14 (2000).
Gray, J. A. The Neuropsychology of Anxiety 1st edn (Oxford Univ. Press, 1982).
Gray, J. A. & McNaughton, N. The Neuropsychology of Anxiety 2nd edn (Oxford Univ. Press, 2000).
Hasler, G. et al. Cerebral blood flow in immediate and sustained anxiety. J. Neurosci. 27, 6313–6319 (2007).
Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).
Holick, K. A., Lee, D. C., Hen, R. & Dulawa, S. C. Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 33, 406–417 (2008).
Deacon, R. M., Bannerman, D. M. & Rawlins, J. N. Anxiolytic effects of cytotoxic hippocampal lesions in rats. Behav. Neurosci. 116, 494–497 (2002).
Treit, D. & Menard, J. Dissociations among the anxiolytic effects of septal, hippocampal, and amygdaloid lesions. Behav. Neurosci. 111, 653–658 (1997).
Barkus, C. et al. Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion. Eur. J. Pharmacol. 626, 49–56 (2010).
Witter, M. P. A survey of the anatomy of the hippocampal formation, with emphasis on the septotemporal organization of its intrinsic and extrinsic connections. Adv. Exp. Med. Biol. 203, 67–82 (1986).
Siegel, A. & Tassoni, J. P. Differential efferent projections from the ventral and dorsal hippocampus of the cat. Brain, Behav. Evol. 4, 185–200 (1971).
Moser, M. B. & Moser, E. I. Functional differentiation in the hippocampus. Hippocampus 8, 608–619 (1998).
Swanson, L. W. & Cowan, W. M. An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat. J. Comp. Neurol. 172, 49–84 (1977).
Moser, E., Moser, M. B. & Andersen, P. Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J. Neurosci. 13, 3916–3925 (1993).
Moser, M. B., Moser, E. I., Forrest, E., Andersen, P. & Morris, R. G. Spatial learning with a minislab in the dorsal hippocampus. Proc. Natl Acad. Sci. USA 92, 9697–9701 (1995).
Hock, B. J. Jr & Bunsey, M. D. Differential effects of dorsal and ventral hippocampal lesions. J. Neurosci. 18, 7027–7032 (1998).
Bannerman, D. M. et al. Double dissociation of function within the hippocampus: spatial memory and hyponeophagia. Behav. Neurosci. 116, 884–901 (2002).
Pothuizen, H. H., Zhang, W. N., Jongen-Relo, A. L., Feldon, J. & Yee, B. K. Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory. Eur. J. Neurosci. 19, 705–712 (2004).
Bannerman, D. M. et al. Ventral hippocampal lesions affect anxiety but not spatial learning. Behav. Brain Res. 139, 197–213 (2003).
Kjelstrup, K. G. et al. Reduced fear expression after lesions of the ventral hippocampus. Proc. Natl Acad. Sci. USA 99, 10825–10830 (2002).
McHugh, S. B., Deacon, R. M., Rawlins, J. N. & Bannerman, D. M. Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behav. Neurosci. 118, 63–78 (2004).
Chudasama, Y., Wright, K. S. & Murray, E. A. Hippocampal lesions in rhesus monkeys disrupt emotional responses but not reinforcer devaluation effects. Biol. Psychiatry 63, 1084–1091 (2008).
Pentkowski, N. S., Blanchard, D. C., Lever, C., Litvin, Y. & Blanchard, R. J. Effects of lesions to the dorsal and ventral hippocampus on defensive behaviors in rats. Eur. J. Neurosci. 23, 2185–2196 (2006).
Maren, S. Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in the acquisition and expression of Pavlovian fear conditioning in rats. Behav. Neurosci. 113, 283–290 (1999).
Richmond, M. A. et al. Dissociating context and space within the hippocampus: effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning. Behav. Neurosci. 113, 1189–1203 (1999).
McHugh, S. B., Campbell, T. G., Taylor, A. M., Rawlins, J. N. & Bannerman, D. M. A role for dorsal and ventral hippocampus in inter-temporal choice cost–benefit decision making. Behav. Neurosci. 122, 1–8 (2008).
Hartley, T., Maguire, E. A., Spiers, H. J. & Burgess, N. The well-worn route and the path less traveled: distinct neural bases of route following and wayfinding in humans. Neuron 37, 877–888 (2003).
Kumaran, D. & Maguire, E. A. The human hippocampus: cognitive maps or relational memory? J. Neurosci. 25, 7254–7259 (2005).
Maguire, E. A., Frackowiak, R. S. & Frith, C. D. Recalling routes around london: activation of the right hippocampus in taxi drivers. J. Neurosci. 17, 7103–7110 (1997).
Maguire, E. A. et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc. Natl Acad. Sci. USA 97, 4398–4403 (2000).
Alvarez, R. P., Biggs, A., Chen, G., Pine, D. S. & Grillon, C. Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J. Neurosci. 28, 6211–6219 (2008).
Fanselow, M. S. & Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).
Bast, T., Wilson, I. A., Witter, M. P. & Morris, R. G. From rapid place learning to behavioral performance: a key role for the intermediate hippocampus. PLoS Biol. 7, e1000089 (2009).
Vinogradova, O. S. in The Hippocampus Vol. 2 (eds Isaacson, R. I. & Pribram, K. H.) 3–69 (Plenum, 1975).
Jarrard, L. & Isaacson, R. L. Runway response perseveration in the hippocampectomised rat: determined by extinction variables. Nature 207, 109–110 (1965).
Clark, C. V. & Isaacson, R. L. Effect of bilateral hippocampal ablation on Drl performance. J. Comp. Physiol. Psychol. 59, 137–140 (1965).
Douglas, R. J. The hippocampus and behavior. Psychol. Bull. 67, 416–422 (1967).
Davidson, T. L. & Jarrard, L. E. The hippocampus and inhibitory learning: a 'Gray' area? Neurosci. Biobehav Rev. 28, 261–271 (2004).
Kimble, D. P. & Kimble, R. J. Hippocampectomy and response perseveration in the rat. J. Comp. Physiol. Psychol. 60, 474–476 (1965).
Lisman, J. E. & Grace, A. A. The hippocampal–VTA loop: controlling the entry of information into long-term memory. Neuron 46, 703–713 (2005).
Hollerman, J. R. & Schultz, W. Dopamine neurons report an error in the temporal prediction of reward during learning. Nature Neurosci. 1, 304–309 (1998).
Ploghaus, A. et al. Learning about pain: the neural substrate of the prediction error for aversive events. Proc. Natl Acad. Sci. USA 97, 9281–9286 (2000).
Han, J. S., Gallagher, M. & Holland, P. Hippocampal lesions disrupt decrements but not increments in conditioned stimulus processing. J. Neurosci. 15, 7323–7329 (1995).
Kumaran, D. & Maguire, E. A. Match mismatch processes underlie human hippocampal responses to associative novelty. J. Neurosci. 27, 8517–8524 (2007).
Kumaran, D. & Maguire, E. A. An unexpected sequence of events: mismatch detection in the human hippocampus. PLoS Biol. 4, e424 (2006).
O'Keefe, J. Place units in the hippocampus of the freely moving rat. Exp. Neurol. 51, 78–109 (1976).
Fyhn, M., Molden, S., Hollup, S., Moser, M. B. & Moser, E. Hippocampal neurons responding to first-time dislocation of a target object. Neuron 35, 555–566 (2002).
Honey, R. C. & Good, M. Associative components of recognition memory. Curr. Opin. Neurobiol. 10, 200–204 (2000).
Honey, R. C., Watt, A. & Good, M. Hippocampal lesions disrupt an associative mismatch process. J. Neurosci. 18, 2226–2230 (1998).
Resnik, E., McFarland, J. M., Sprengel, R., Sakmann, B. & Mehta, M. R. The effects of GluA1 deletion on the hippocampal population code for position. J. Neurosci. 32, 8952–8968 (2012).
Reisel, D. et al. Spatial memory dissociations in mice lacking GluR1. Nature Neurosci. 5, 868–873 (2002).
Zamanillo, D. et al. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811 (1999).
Korotkova, T., Fuchs, E. C., Ponomarenko, A., von Engelhardt, J. & Monyer, H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68, 557–569 (2010).
Allen, K., Fuchs, E. C., Jaschonek, H., Bannerman, D. M. & Monyer, H. Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory. J. Neurosci. 31, 6542–6552 (2011).
Caputi, A., Fuchs, E. C., Allen, K., Le Magueresse, C. & Monyer, H. Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity. PLoS ONE 7, e37318 (2012).
Lisman, J. E. Role of the dual entorhinal inputs to hippocampus: a hypothesis based on cue/action (non-self/self) couplets. Prog. Brain Res. 163, 615–625 (2007).
Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).
Kessels, H. W. & Malinow, R. Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009).
Erickson, M. A., Maramara, L. A. & Lisman, J. A single brief burst induces GluR1-dependent associative short-term potentiation: a potential mechanism for short-term memory. J. Cogn. Neurosci. 22, 2530–2540 (2010).
Hoffman, D. A., Sprengel, R. & Sakmann, B. Molecular dissection of hippocampal theta-burst pairing potentiation. Proc. Natl Acad. Sci. USA 99, 7740–7745 (2002).
Romberg, C. et al. Induction and expression of GluA1 (GluR-A)-independent LTP in the hippocampus. Eur. J. Neurosci. 29, 1141–1152 (2009).
Schmitt, W. B. et al. Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice. Nature Neurosci. 8, 270–272 (2005).
Sanderson, D. J. et al. Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory. Behav. Neurosci. 121, 559–569 (2007).
Sanderson, D. J. et al. Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory. Learn. Mem. 18, 181–190 (2011).
Sanderson, D. J., Sprengel, R., Seeburg, P. H. & Bannerman, D. M. Deletion of the GluA1 AMPA receptor subunit alters the expression of short-term memory. Learn. Mem. 18, 128–131 (2011).
Wagner, A. R. in Information Processing in Animals: Memory Mechanisms (eds Spear, N. E. & Miller, R. R.) 5–47 (Erlbaum, 1981).
Brandon, S. E., Vogel, E. H. & Wagner, A. R. Stimulus representation in SOP: I. theoretical rationalization and some implications. Behav. Processes 62, 5–25 (2003).
Fuchs, E. C. et al. Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron 53, 591–604 (2007).
Murray, A. J. et al. Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. Nature Neurosci. 14, 297–299 (2011).
Gray, C. M. & Singer, W. Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex. Proc. Natl Acad. Sci. USA 86, 1698–1702 (1989).
Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsaki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).
Wilson, M. A. & McNaughton, B. L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993).
This work was supported by the Wellcome trust (grants 074385 and 087736 to D.M.B.), the European Research Council (GABAcellsAndMemory grant 250047 to H.M.), the Deutsche Forschungsgemeinschaft (SFB 636/A4 to R.S.) and the Max Planck Society (to R.S. and P.H.S.).
The authors declare no competing financial interests.
(2-amino-5-phosphopentanoate). A competitive antagonist of the NMDA-type glutamate receptor. The drug competes with glutamate to bind to the NMDA receptor and thus reduces the activity of these receptors.
- Boundary vector cells
The firing of these cells depends solely on the animal's location relative to environmental boundaries and is independent of the animal's heading direction.
A term to describe when an experimental manipulation (for example, a lesion, genetic modification or drug treatment) affects performance on one behavioural task but not another. This is taken to suggest that different neural substrates may underlie the two behaviours.
- Double dissociation
A term to describe when a given experimental manipulation affects task A but not task B, whereas a second manipulation affects task B but does not affect task A. A double dissociation is evidence that these behaviours must be supported by different neural substrates.
- Grid cells
Cells that have been found in layer 2/3 of the medial entorhinal cortex and that fire at several regularly spaced locations (unlike hippocampal place cells, which fire only in one part of a given environment), with marked inhibition of firing outside these locations.
- Head direction cells
Cells that are sensitive to the orientation of the animal's head with respect to the environmental frame, irrespective of the animal's spatial location within that environment. They signal a single preferred head direction, irrespective of body-orientation or current position; whether the animal is moving or stationary.
- Place cells
Cells that selectively increase their firing rate only when the animal occupies a well-defined, small patch of the environment (the place field), and they rarely fire outside this region. Place cells are usually recorded in the hippocampus proper, but they are also present in other areas of the hippocampal formation (for example, the entorhinal cortex, subiculum, presubiculum and parasubiculum).
- Spatial reference memory
(SRM).The ability to learn a consistent, fixed response to a spatial stimulus, reflecting a constant association between that spatial location and an outcome. For example, an animal will need to learn the spatial location of its home burrow or a reliable water source that is constant within the environment.
- Spatial working memory
(SWM). The ability to maintain trial-specific information for a limited period of time so that spatial responses can be made in a flexible manner from trial to trial. This is the basis of foraging behaviour (for example, remembering where you have just been so that you can adopt an efficient search strategy).
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Bannerman, D., Sprengel, R., Sanderson, D. et al. Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci 15, 181–192 (2014). https://doi.org/10.1038/nrn3677
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