Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Synaptic integrative mechanisms for spatial cognition

Nature Neuroscience volume 20, pages 1483–1492 (2017)Cite this article

Subjects

Abstract

Synaptic integrative mechanisms have profound effects on electrical signaling in the brain that, although largely hidden from recording methods that observe the spiking activity of neurons, may be critical for the encoding, storage and retrieval of information. Here we review roles for synaptic integrative mechanisms in the selection, generation and plasticity of place and grid fields, and in related temporal codes for the representation of space. We outline outstanding questions and challenges in the testing of hypothesized models for spatial computation and memory.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Membrane potential ramp and intracellular phase precession during place and grid field crossings.
Figure 2: Excitability and place cell selection.
Figure 3: Candidate models of nonlinear integration during firing field crossings.
Figure 4: A comparison of the effects of local inhibition on visual and spatial receptive fields.
Figure 5: Theta resonant responses of hippocampal neurons.

Similar content being viewed by others

References

  1. O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Clarendon Press, 1978).

  2. Redish, A.D. Beyond the Cognitive Map: From Place Cells to Episodic Memory (MIT Press, 1999).

  3. Spruston, N. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci. 9, 206–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Häusser, M., Spruston, N. & Stuart, G.J. Diversity and dynamics of dendritic signaling. Science 290, 739–744 (2000).

    Article  PubMed  Google Scholar 

  5. Chadderton, P., Schaefer, A.T., Williams, S.R. & Margrie, T.W. Sensory-evoked synaptic integration in cerebellar and cerebral cortical neurons. Nat. Rev. Neurosci. 15, 71–83 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. LeCun, Y., Bengio, Y. & Hinton, G. Deep learning. Nature 521, 436–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Häusser, M. & Mel, B. Dendrites: bug or feature? Curr. Opin. Neurobiol. 13, 372–383 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. O'Keefe, J., Burgess, N., Donnett, J.G., Jeffery, K.J. & Maguire, E.A. Place cells, navigational accuracy, and the human hippocampus. Phil. Trans. R. Soc. Lond. B 353, 1333–1340 (1998).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. Harvey, C.D., Collman, F., Dombeck, D.A. & Tank, D.W. Intracellular dynamics of hippocampal place cells during virtual navigation. Nature 461, 941–946 (2009).By developing methods for patch-clamp recording from CA1 pyramidal cells in awake mice navigating in a virtual environment, this study revealed the membrane potential dynamics that underlie place cell firing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schmidt-Hieber, C. & Häusser, M. Cellular mechanisms of spatial navigation in the medial entorhinal cortex. Nat. Neurosci. 16, 325–331 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Domnisoru, C., Kinkhabwala, A.A. & Tank, D.W. Membrane potential dynamics of grid cells. Nature 495, 199–204 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hartley, T., Burgess, N., Lever, C., Cacucci, F. & O'Keefe, J. Modeling place fields in terms of the cortical inputs to the hippocampus. Hippocampus 10, 369–379 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Burgess, N. & O'Keefe, J. Models of place and grid cell firing and theta rhythmicity. Curr. Opin. Neurobiol. 21, 734–744 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Solstad, T., Moser, E.I. & Einevoll, G.T. From grid cells to place cells: a mathematical model. Hippocampus 16, 1026–1031 (2006).

    Article  PubMed  Google Scholar 

  16. Eichenbaum, H., Dudchenko, P., Wood, E., Shapiro, M. & Tanila, H. The hippocampus, memory, and place cells: is it spatial memory or a memory space? Neuron 23, 209–226 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Burgess, N., Maguire, E.A. & O'Keefe, J. The human hippocampus and spatial and episodic memory. Neuron 35, 625–641 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Chrobak, J.J., Lörincz, A. & Buzsáki, G. Physiological patterns in the hippocampo-entorhinal cortex system. Hippocampus 10, 457–465 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. O'Keefe, J. Place units in the hippocampus of the freely moving rat. Exp. Neurol. 51, 78–109 (1976).

    Article  CAS  PubMed  Google Scholar 

  20. Skaggs, W.E., McNaughton, B.L., Wilson, M.A. & Barnes, C.A. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus 6, 149–172 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Chadwick, A., van Rossum, M.C. & Nolan, M.F. Flexible theta sequence compression mediated via phase precessing interneurons. eLife 5, e20349 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ziv, Y. et al. Long-term dynamics of CA1 hippocampal place codes. Nat. Neurosci. 16, 264–266 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rich, P.D., Liaw, H.-P. & Lee, A.K. Place cells. Large environments reveal the statistical structure governing hippocampal representations. Science 345, 814–817 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Thompson, L.T. & Best, P.J. Place cells and silent cells in the hippocampus of freely-behaving rats. J. Neurosci. 9, 2382–2390 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Epsztein, J., Brecht, M. & Lee, A.K. Intracellular determinants of hippocampal CA1 place and silent cell activity in a novel environment. Neuron 70, 109–120 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cohen, J.D., Bolstad, M. & Lee, A.K. Experience-dependent shaping of hippocampal CA1 intracellular activity in novel and familiar environments. eLife 6, e23040 (2017).This study provides fundamental insight into the mechanisms of place cell formation. Using intracellular recordings from place cells in mice navigating in novel or familiar virtual environments, the authors show how membrane potential dynamics change during the development of novel place fields.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Silva, A.J., Zhou, Y., Rogerson, T., Shobe, J. & Balaji, J. Molecular and cellular approaches to memory allocation in neural circuits. Science 326, 391–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou, Y. et al. CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nat. Neurosci. 12, 1438–1443 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yiu, A.P. et al. Neurons are recruited to a memory trace based on relative neuronal excitability immediately before training. Neuron 83, 722–735 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Rashid, A.J. et al. Competition between engrams influences fear memory formation and recall. Science 353, 383–387 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rubin, A., Geva, N., Sheintuch, L. & Ziv, Y. Hippocampal ensemble dynamics timestamp events in long-term memory. eLife 4, e12247 (2015).This study reveals a temporal code for time-stamping events. By following the activity of populations of place cells over several weeks, the authors found that the timing of experience on a timescale of days can be decoded from CA1 population activity independently of context.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Cai, D.J. et al. A shared neural ensemble links distinct contextual memories encoded close in time. Nature 534, 115–118 (2016).This study tests hypothesized roles of excitability in memory allocation within CA1. Convergent evidence from imaging of place cell activity, anatomical tagging of activated cells, and behavioral experiments supports the idea that memories of events that are close in time are allocated to overlapping populations of neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kastellakis, G., Silva, A.J. & Poirazi, P. Linking memories across time via neuronal and dendritic overlaps in model neurons with active dendrites. Cell Rep. 17, 1491–1504 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dudek, S.M. & Fields, R.D. Somatic action potentials are sufficient for late-phase LTP-related cell signaling. Proc. Natl. Acad. Sci. USA 99, 3962–3967 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Deisseroth, K., Bito, H. & Tsien, R.W. Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89–101 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Lopez de Armentia, M. et al. cAMP response element-binding protein-mediated gene expression increases the intrinsic excitability of CA1 pyramidal neurons. J. Neurosci. 27, 13909–13918 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Disterhoft, J.F. & Oh, M.M. Learning, aging and intrinsic neuronal plasticity. Trends Neurosci. 29, 587–599 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Lovett-Barron, M. et al. Dendritic inhibition in the hippocampus supports fear learning. Science 343, 857–863 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stefanelli, T., Bertollini, C., Lüscher, C., Muller, D. & Mendez, P. Hippocampal somatostatin interneurons control the size of neuronal memory ensembles. Neuron 89, 1074–1085 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Mankin, E.A. et al. Neuronal code for extended time in the hippocampus. Proc. Natl. Acad. Sci. USA 109, 19462–19467 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Mankin, E.A., Diehl, G.W., Sparks, F.T., Leutgeb, S. & Leutgeb, J.K. Hippocampal CA2 activity patterns change over time to a larger extent than between spatial contexts. Neuron 85, 190–201 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lipowsky, R., Gillessen, T. & Alzheimer, C. Dendritic Na+ channels amplify EPSPs in hippocampal CA1 pyramidal cells. J. Neurophysiol. 76, 2181–2191 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Magee, J.C. Dendritic lh normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci. 2, 508–514 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Ngo-Anh, T.J. et al. SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat. Neurosci. 8, 642–649 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Losonczy, A., Makara, J.K. & Magee, J.C. Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452, 436–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Amaral, D.G. & Witter, M.P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989).

    Article  CAS  PubMed  Google Scholar 

  47. Freund, T.F. & Buzsáki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Middleton, S.J. & McHugh, T.J. Silencing CA3 disrupts temporal coding in the CA1 ensemble. Nat. Neurosci. 19, 945–951 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Schlesiger, M.I. et al. The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity. Nat. Neurosci. 18, 1123–1132 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Magee, J.C. Dendritic integration of excitatory synaptic input. Nat. Rev. Neurosci. 1, 181–190 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Nolan, M.F. et al. A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 119, 719–732 (2004).

    CAS  PubMed  Google Scholar 

  52. Tsay, D., Dudman, J.T. & Siegelbaum, S.A. HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons. Neuron 56, 1076–1089 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cai, X. et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44, 351–364 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Lee, D., Lin, B.-J. & Lee, A.K. Hippocampal place fields emerge upon single-cell manipulation of excitability during behavior. Science 337, 849–853 (2012).This work reveals surprisingly nonlinear properties of place cells. The authors obtained intracellular recordings from hippocampal neurons in freely navigating mice. They show that silent cells without any spatial modulation of membrane potential can be turned into place cells by sustained depolarization.

    Article  CAS  PubMed  Google Scholar 

  55. Nevian, T., Larkum, M.E., Polsky, A. & Schiller, J. Properties of basal dendrites of layer 5 pyramidal neurons: a direct patch-clamp recording study. Nat. Neurosci. 10, 206–214 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Druckmann, S. et al. Structured synaptic connectivity between hippocampal regions. Neuron 81, 629–640 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Wilson, D.E., Whitney, D.E., Scholl, B. & Fitzpatrick, D. Orientation selectivity and the functional clustering of synaptic inputs in primary visual cortex. Nat. Neurosci. 19, 1003–1009 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Iacaruso, M.F., Gasler, I.T. & Hofer, S.B. Synaptic organization of visual space in primary visual cortex. Nature 547, 449–452 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Haider, B., Häusser, M. & Carandini, M. Inhibition dominates sensory responses in the awake cortex. Nature 493, 97–100 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Atallah, B.V., Bruns, W., Carandini, M. & Scanziani, M. Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli. Neuron 73, 159–170 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Atallah, B.V., Scanziani, M. & Carandini, M. Atallah et al. reply. Nature 508, E3 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Grienberger, C., Milstein, A.D., Bittner, K.C., Romani, S. & Magee, J.C. Inhibitory suppression of heterogeneously tuned excitation enhances spatial coding in CA1 place cells. Nat. Neurosci. 20, 417–426 (2017).Using optogenetic silencing of hippocampal interneurons in conjunction with intracellular recordings from place cells, the authors of this study addressed the role of inhibition in the shaping of place fields. They show that uniform inhibition can contribute to place field tuning, probably by suppressing firing outside of the place field.

    Article  CAS  PubMed  Google Scholar 

  63. Wilson, N.R., Runyan, C.A., Wang, F.L. & Sur, M. Division and subtraction by distinct cortical inhibitory networks in vivo. Nature 488, 343–348 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee, S.-H. et al. Activation of specific interneurons improves V1 feature selectivity and visual perception. Nature 488, 379–383 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cottam, J.C.H., Smith, S.L. & Häusser, M. Target-specific effects of somatostatin-expressing interneurons on neocortical visual processing. J. Neurosci. 33, 19567–19578 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Royer, S. et al. Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition. Nat. Neurosci. 15, 769–775 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yoon, K. et al. Specific evidence of low-dimensional continuous attractor dynamics in grid cells. Nat. Neurosci. 16, 1077–1084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fyhn, M., Hafting, T., Treves, A., Moser, M.-B. & Moser, E.I. Hippocampal remapping and grid realignment in entorhinal cortex. Nature 446, 190–194 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Pastoll, H., Ramsden, H.L. & Nolan, M.F. Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fields. Front. Neural Circuits 6, 17 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ray, S. et al. Grid-layout and theta-modulation of layer 2 pyramidal neurons in medial entorhinal cortex. Science 343, 891–896 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Couey, J.J. et al. Recurrent inhibitory circuitry as a mechanism for grid formation. Nat. Neurosci. 16, 318–324 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Pastoll, H., Solanka, L., van Rossum, M.C.W. & Nolan, M.F. Feedback inhibition enables θ-nested γ oscillations and grid firing fields. Neuron 77, 141–154 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Nolan, M.F., Dudman, J.T., Dodson, P.D. & Santoro, B. HCN1 channels control resting and active integrative properties of stellate cells from layer II of the entorhinal cortex. J. Neurosci. 27, 12440–12451 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Giocomo, L.M. et al. Grid cells use HCN1 channels for spatial scaling. Cell 147, 1159–1170 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Robinson, R.B. & Siegelbaum, S.A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol. 65, 453–480 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Garden, D.L.F., Dodson, P.D., O'Donnell, C., White, M.D. & Nolan, M.F. Tuning of synaptic integration in the medial entorhinal cortex to the organization of grid cell firing fields. Neuron 60, 875–889 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Giocomo, L.M., Zilli, E.A., Fransén, E. & Hasselmo, M.E. Temporal frequency of subthreshold oscillations scales with entorhinal grid cell field spacing. Science 315, 1719–1722 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schmidt-Hieber, C. et al. Active dendritic integration as a mechanism for robust and precise grid cell firing. Nat. Neurosci. 20, 1114–1121 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Palmer, L.M. et al. NMDA spikes enhance action potential generation during sensory input. Nat. Neurosci. 17, 383–390 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Lavzin, M., Rapoport, S., Polsky, A., Garion, L. & Schiller, J. Nonlinear dendritic processing determines angular tuning of barrel cortex neurons in vivo. Nature 490, 397–401 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Smith, S.L., Smith, I.T., Branco, T. & Häusser, M. Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo. Nature 503, 115–120 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Poirazi, P. & Mel, B.W. Impact of active dendrites and structural plasticity on the memory capacity of neural tissue. Neuron 29, 779–796 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Buzsáki, G. & Moser, E.I. Memory, navigation and theta rhythm in the hippocampal-entorhinal system. Nat. Neurosci. 16, 130–138 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. Bliss, T.V. & Collingridge, G.L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  Google Scholar 

  88. Kentros, C. et al. Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science 280, 2121–2126 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. McHugh, T.J., Blum, K.I., Tsien, J.Z., Tonegawa, S. & Wilson, M.A. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell 87, 1339–1349 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Moosmang, S. et al. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. J. Neurosci. 25, 9883–9892 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sheffield, M.E.J. & Dombeck, D.A. Calcium transient prevalence across the dendritic arbour predicts place field properties. Nature 517, 200–204 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Takahashi, H. & Magee, J.C. Pathway interactions and synaptic plasticity in the dendritic tuft regions of CA1 pyramidal neurons. Neuron 62, 102–111 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Bittner, K.C. et al. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons. Nat. Neurosci. 18, 1133–1142 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bittner, K.C., Milstein, A.D., Grienberger, C., Romani, S. & Magee, J.C. Behavioral time scale synaptic plasticity underlies CA1 place fields. Science 357, 1033–1036 (2017).This study reports an unusual form of synaptic plasticity in CA1 pyramidal cells, whereby a single pairing of pre- and postsynaptic activity within a time window of several seconds produces long-term potentiation of the synaptic response. Such a pairing paradigm may store events that occur at behavioral timescales.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Golding, N.L., Staff, N.P. & Spruston, N. Dendritic spikes as a mechanism for cooperative long-term potentiation. Nature 418, 326–331 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Dudman, J.T., Tsay, D. & Siegelbaum, S.A. A role for synaptic inputs at distal dendrites: instructive signals for hippocampal long-term plasticity. Neuron 56, 866–879 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Frank, L.M., Stanley, G.B. & Brown, E.N. Hippocampal plasticity across multiple days of exposure to novel environments. J. Neurosci. 24, 7681–7689 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hill, A.J. First occurrence of hippocampal spatial firing in a new environment. Exp. Neurol. 62, 282–297 (1978).

    Article  CAS  PubMed  Google Scholar 

  99. Brandalise, F. & Gerber, U. Mossy fiber-evoked subthreshold responses induce timing-dependent plasticity at hippocampal CA3 recurrent synapses. Proc. Natl. Acad. Sci. USA 111, 4303–4308 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Brandalise, F., Carta, S., Helmchen, F., Lisman, J. & Gerber, U. Dendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells. Nat. Commun. 7, 13480 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lörincz, A., Notomi, T., Tamás, G., Shigemoto, R. & Nusser, Z. Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat. Neurosci. 5, 1185–1193 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Hussaini, S.A., Kempadoo, K.A., Thuault, S.J., Siegelbaum, S.A. & Kandel, E.R. Increased size and stability of CA1 and CA3 place fields in HCN1 knockout mice. Neuron 72, 643–653 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Maroso, M. et al. Cannabinoid control of learning and memory through HCN channels. Neuron 89, 1059–1073 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Magee, J.C. Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci. 2, 848 (1999).

    Article  CAS  PubMed  Google Scholar 

  105. Buzsáki, G. Theta oscillations in the hippocampus. Neuron 33, 325–340 (2002).

    Article  PubMed  Google Scholar 

  106. O'Keefe, J. & Recce, M.L. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3, 317–330 (1993).

    Article  CAS  PubMed  Google Scholar 

  107. Bender, F. et al. Theta oscillations regulate the speed of locomotion via a hippocampus to lateral septum pathway. Nat. Commun. 6, 8521 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Freund, T.F. & Antal, M. GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus. Nature 336, 170–173 (1988).

    Article  CAS  PubMed  Google Scholar 

  109. Boyce, R., Glasgow, S.D., Williams, S. & Adamantidis, A. Causal evidence for the role of REM sleep theta rhythm in contextual memory consolidation. Science 352, 812–816 (2016).

    Article  CAS  PubMed  Google Scholar 

  110. Gonzalez-Sulser, A. et al. GABAergic projections from the medial septum selectively inhibit interneurons in the medial entorhinal cortex. J. Neurosci. 34, 16739–16743 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tóth, K., Freund, T.F. & Miles, R. Disinhibition of rat hippocampal pyramidal cells by GABAergic afferents from the septum. J. Physiol. (Lond.) 500, 463–474 (1997).

    Article  Google Scholar 

  112. Mizuseki, K., Sirota, A., Pastalkova, E. & Buzsáki, G. Theta oscillations provide temporal windows for local circuit computation in the entorhinal-hippocampal loop. Neuron 64, 267–280 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pike, F.G. et al. Distinct frequency preferences of different types of rat hippocampal neurones in response to oscillatory input currents. J. Physiol. (Lond.) 529, 205–213 (2000).

    Article  CAS  Google Scholar 

  114. Zemankovics, R., Káli, S., Paulsen, O., Freund, T.F. & Hájos, N. Differences in subthreshold resonance of hippocampal pyramidal cells and interneurons: the role of h-current and passive membrane characteristics. J. Physiol. (Lond.) 588, 2109–2132 (2010).

    Article  CAS  Google Scholar 

  115. Leung, L.S. & Yu, H.W. Theta-frequency resonance in hippocampal CA1 neurons in vitro demonstrated by sinusoidal current injection. J. Neurophysiol. 79, 1592–1596 (1998).

    Article  CAS  PubMed  Google Scholar 

  116. Erchova, I., Kreck, G., Heinemann, U. & Herz, A.V.M. Dynamics of rat entorhinal cortex layer II and III cells: characteristics of membrane potential resonance at rest predict oscillation properties near threshold. J. Physiol. (Lond.) 560, 89–110 (2004).

    Article  CAS  Google Scholar 

  117. Hu, H., Vervaeke, K. & Storm, J.F. Two forms of electrical resonance at theta frequencies, generated by M-current, h-current and persistent Na+ current in rat hippocampal pyramidal cells. J. Physiol. (Lond.) 545, 783–805 (2002).

    Article  CAS  Google Scholar 

  118. Peters, H.C., Hu, H., Pongs, O., Storm, J.F. & Isbrandt, D. Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nat. Neurosci. 8, 51–60 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Borel, M., Guadagna, S., Jang, H.J., Kwag, J. & Paulsen, O. Frequency dependence of CA3 spike phase response arising from h-current properties. Front. Cell. Neurosci. 7, 263 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ness, T.V., Remme, M.W.H. & Einevoll, G.T. Active subthreshold dendritic conductances shape the local field potential. J. Physiol. (Lond.) 594, 3809–3825 (2016).

    Article  CAS  Google Scholar 

  121. Stark, E. et al. Inhibition-induced theta resonance in cortical circuits. Neuron 80, 1263–1276 (2013).The experiments in this study provide evidence for theta-frequency resonance in behaving animals. Intriguingly, resonant responses of CA1 pyramidal cells were observed in response to the activation of PV interneurons, but not after direct activation.

    Article  CAS  PubMed  Google Scholar 

  122. Alonso, A. & Llinás, R.R. Subthreshold Na+-dependent theta-like rhythmicity in stellate cells of entorhinal cortex layer II. Nature 342, 175–177 (1989).

    Article  CAS  PubMed  Google Scholar 

  123. Leung, L.W. & Yim, C.Y. Intrinsic membrane potential oscillations in hippocampal neurons in vitro. Brain Res. 553, 261–274 (1991).

    Article  CAS  PubMed  Google Scholar 

  124. Fernandez, F.R. & White, J.A. Artificial synaptic conductances reduce subthreshold oscillations and periodic firing in stellate cells of the entorhinal cortex. J. Neurosci. 28, 3790–3803 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Jaramillo, J. & Kempter, R. Phase precession: a neural code underlying episodic memory? Curr. Opin. Neurobiol. 43, 130–138 (2017).

    Article  CAS  PubMed  Google Scholar 

  126. Leung, L.S. A model of intracellular θ phase precession dependent on intrinsic subthreshold membrane currents. J. Neurosci. 31, 12282–12296 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Harris, K.D. et al. Spike train dynamics predicts theta-related phase precession in hippocampal pyramidal cells. Nature 417, 738–741 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Magee, J.C. Dendritic mechanisms of phase precession in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 86, 528–532 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Mehta, M.R., Lee, A.K. & Wilson, M.A. Role of experience and oscillations in transforming a rate code into a temporal code. Nature 417, 741–746 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Mehta, M.R., Quirk, M.C. & Wilson, M.A. Experience-dependent asymmetric shape of hippocampal receptive fields. Neuron 25, 707–715 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Chadwick, A., van Rossum, M.C.W. & Nolan, M.F. Independent theta phase coding accounts for CA1 population sequences and enables flexible remapping. eLife 4, e03542 (2015).

    Article  PubMed Central  Google Scholar 

  132. Eggink, H., Mertens, P., Storm, E. & Giocomo, L.M. Hyperpolarization-activated cyclic nucleotide-gated 1 independent grid cell-phase precession in mice. Hippocampus 24, 249–256 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Kim, S., Guzman, S.J., Hu, H. & Jonas, P. Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons. Nat. Neurosci. 15, 600–606 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Makara, J.K. & Magee, J.C. Variable dendritic integration in hippocampal CA3 pyramidal neurons. Neuron 80, 1438–1450 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Krueppel, R., Remy, S. & Beck, H. Dendritic integration in hippocampal dentate granule cells. Neuron 71, 512–528 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Branco, T., Clark, B.A. & Häusser, M. Dendritic discrimination of temporal input sequences in cortical neurons. Science 329, 1671–1675 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Stocca, G., Schmidt-Hieber, C. & Bischofberger, J. Differential dendritic Ca2+ signalling in young and mature hippocampal granule cells. J. Physiol. (Lond.) 586, 3795–3811 (2008).

    Article  CAS  Google Scholar 

  138. McHugh, T.J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Chavlis, S., Petrantonakis, P.C. & Poirazi, P. Dendrites of dentate gyrus granule cells contribute to pattern separation by controlling sparsity. Hippocampus 27, 89–110 (2017).

    Article  PubMed  Google Scholar 

  140. Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Subthreshold dendritic signal processing and coincidence detection in dentate gyrus granule cells. J. Neurosci. 27, 8430–8441 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Valero, M. et al. Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples. Nat. Neurosci. 18, 1281–1290 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Gan, J., Weng, S.-M., Pernía-Andrade, A.J., Csicsvari, J. & Jonas, P. Phase-locked inhibition, but not excitation, underlies hippocampal ripple oscillations in awake mice in vivo. Neuron 93, 308–314 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Cobb, S. & Lawrence, J.J. Neuromodulation of hippocampal cells and circuits. In Hippocampal Microcircuits: A Computational Modeler's Resource Book (eds. Cutsuridis, V., Graham, B.P., Cobb, S. & Vida, I.) 187–246 (Springer, 2010).

  144. Marder, E. Neuromodulation of neuronal circuits: back to the future. Neuron 76, 1–11 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Martinello, K. et al. Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells. Neuron 85, 346–363 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hasselmo, M.E., Hay, J., Ilyn, M. & Gorchetchnikov, A. Neuromodulation, theta rhythm and rat spatial navigation. Neural Netw. 15, 689–707 (2002).

    Article  PubMed  Google Scholar 

  147. Kramer, R.H., Mourot, A. & Adesnik, H. Optogenetic pharmacology for control of native neuronal signaling proteins. Nat. Neurosci. 16, 816–823 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Hamel, E.J.O., Grewe, B.F., Parker, J.G. & Schnitzer, M.J. Cellular level brain imaging in behaving mammals: an engineering approach. Neuron 86, 140–159 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Gong, Y. et al. High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor. Science 350, 1361–1366 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Koenig, J., Linder, A.N., Leutgeb, J.K. & Leutgeb, S. The spatial periodicity of grid cells is not sustained during reduced theta oscillations. Science 332, 592–595 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank N. Rochefort and G. Sürmeli for comments on the manuscript, A. Lee for sharing data before publication (ref. 26), and G. Buzsáki and E. Stark for sharing material for the generation of figures. This work was funded in part by the BBSRC (grants BB/M025454/1 and BB/L010496/1 to M.F.N.), the Human Frontiers Science Program (grant RGP0062/2014 to M.F.N.), the Wellcome Trust (grant 200855/Z/16/Z to M.F.N.), the Simons Initiative for the Developing Brain (M.F.N.) and the ERC (grant StG 678790 NEWRON to C.S.-H.).

Author information

Authors and Affiliations

  1. Institut Pasteur, Paris, France

    Christoph Schmidt-Hieber

  2. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK

    Matthew F Nolan

Authors
  1. Christoph Schmidt-Hieber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew F Nolan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Christoph Schmidt-Hieber or Matthew F Nolan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schmidt-Hieber, C., Nolan, M. Synaptic integrative mechanisms for spatial cognition. Nat Neurosci 20, 1483–1492 (2017). https://doi.org/10.1038/nn.4652

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4652

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing