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Recurrent inhibitory circuitry as a mechanism for grid formation

Abstract

Grid cells in layer II of the medial entorhinal cortex form a principal component of the mammalian neural representation of space. The firing pattern of a single grid cell has been hypothesized to be generated through attractor dynamics in a network with a specific local connectivity including both excitatory and inhibitory connections. However, experimental evidence supporting the presence of such connectivity among grid cells in layer II is limited. Here we report recordings from more than 600 neuron pairs in rat entorhinal slices, demonstrating that stellate cells, the principal cell type in the layer II grid network, are mainly interconnected via inhibitory interneurons. Using a model attractor network, we demonstrate that stable grid firing can emerge from a simple recurrent inhibitory network. Our findings thus suggest that the observed inhibitory microcircuitry between stellate cells is sufficient to generate grid-cell firing patterns in layer II of the medial entorhinal cortex.

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Figure 1: Recurrent inhibitory connectivity in MEC layer II.
Figure 2: Stellate interconnectivity changes during early postnatal development.
Figure 3: Inhibitory connectivity between stellate cells in MEC layer II mediated by fast-spiking neurons.
Figure 4: Optical stimulation of layer II results in inhibition in stellate cells.
Figure 5: A simple inhibitory network is sufficient to generate grid cell patterns.

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References

  1. 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  Google Scholar 

  2. Sargolini, F. et al. Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science 312, 758–762 (2006).

    Article  CAS  Google Scholar 

  3. Burak, Y. & Fiete, I.R. Accurate path integration in continuous attractor network models of grid cells. PLoS Comput. Biol. 5, e1000291 (2009).

    Article  Google Scholar 

  4. Fuhs, M.C. & Touretzky, D.S. A spin glass model of path integration in rat medial entorhinal cortex. J. Neurosci. 26, 4266–4276 (2006).

    Article  CAS  Google Scholar 

  5. McNaughton, B.L., Battaglia, F.P., Jensen, O., Moser, E.I. & Moser, M.B. Path integration and the neural basis of the ′cognitive map′. Nat. Rev. Neurosci. 7, 663–678 (2006).

    CAS  Google Scholar 

  6. Beed, P. et al. Analysis of excitatory microcircuitry in the medial entorhinal cortex reveals cell-type-specific differences. Neuron 68, 1059–1066 (2010).

    Article  CAS  Google Scholar 

  7. Dhillon, A. & Jones, R.S. Laminar differences in recurrent excitatory transmission in the rat entorhinal cortex in vitro. Neuroscience 99, 413–422 (2000).

    Article  CAS  Google Scholar 

  8. Quilichini, P., Sirota, A. & Buzsaki, G. Intrinsic circuit organization and theta-gamma oscillation dynamics in the entorhinal cortex of the rat. J. Neurosci. 30, 11128–11142 (2010).

    Article  CAS  Google Scholar 

  9. Kumar, S.S., Jin, X., Buckmaster, P.S. & Huguenard, J.R. Recurrent circuits in layer II of medial entorhinal cortex in a model of temporal lobe epilepsy. J. Neurosci. 27, 1239–1246 (2007).

    Article  CAS  Google Scholar 

  10. Alonso, A. & Klink, R. Differential electroresponsiveness of stellate and pyramidal-like cells of medial entorhinal cortex layer II. J. Neurophysiol. 70, 128–143 (1993).

    Article  CAS  Google Scholar 

  11. Klink, R. & Alonso, A. Morphological characteristics of layer II projection neurons in the rat medial entorhinal cortex. Hippocampus 7, 571–583 (1997).

    Article  CAS  Google Scholar 

  12. Canto, C.B. & Witter, M.P. Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex. Hippocampus 22, 1277–1299 (2012).

    Article  Google Scholar 

  13. Varga, C., Lee, S.Y. & Soltesz, I. Target-selective GABAergic control of entorhinal cortex output. Nat. Neurosci. 13, 822–824 (2010).

    Article  CAS  Google Scholar 

  14. Gatome, C.W., Slomianka, L., Lipp, H.P. & Amrein, I. Number estimates of neuronal phenotypes in layer II of the medial entorhinal cortex of rat and mouse. Neuroscience 170, 156–165 (2010).

    Article  CAS  Google Scholar 

  15. Boccara, C.N. et al. Grid cells in pre- and parasubiculum. Nat. Neurosci. 13, 987–994 (2010).

    Article  CAS  Google Scholar 

  16. Burgalossi, A. et al. Microcircuits of functionally identified neurons in the rat medial entorhinal cortex. Neuron 70, 773–786 (2011).

    Article  CAS  Google Scholar 

  17. Silberberg, G. & Markram, H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron 53, 735–746 (2007).

    Article  CAS  Google Scholar 

  18. Giocomo, L.M. & Hasselmo, M.E. Time constants of h current in layer ii stellate cells differ along the dorsal to ventral axis of medial entorhinal cortex. J. Neurosci. 28, 9414–9425 (2008).

    Article  CAS  Google Scholar 

  19. Brun, V.H. et al. Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus 18, 1200–1212 (2008).

    Article  Google Scholar 

  20. Langston, R.F. et al. Development of the spatial representation system in the rat. Science 328, 1576–1580 (2010).

    Article  CAS  Google Scholar 

  21. Hoffman, D.A., Magee, J.C., Colbert, C.M. & Johnston, D.K. + channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons. Nature 387, 869–875 (1997).

    Article  CAS  Google Scholar 

  22. Petreanu, L., Mao, T., Sternson, S.M. & Svoboda, K. The subcellular organization of neocortical excitatory connections. Nature 457, 1142–1145 (2009).

    Article  CAS  Google Scholar 

  23. Jones, R.S. & Buhl, E.H. Basket-like interneurones in layer II of the entorhinal cortex exhibit a powerful NMDA-mediated synaptic excitation. Neurosci. Lett. 149, 35–39 (1993).

    Article  CAS  Google Scholar 

  24. Sills, J.B., Connors, B.W. & Burwell, R.D. Electrophysiological and morphological properties of neurons in layer 5 of the rat postrhinal cortex. Hippocampus 22, 1912–1922 (2012).

    Article  Google Scholar 

  25. Tamamaki, N. & Nojyo, Y. Projection of the entorhinal layer II neurons in the rat as revealed by intracellular pressure-injection of neurobiotin. Hippocampus 3, 471–480 (1993).

    Article  CAS  Google Scholar 

  26. Yizhar, O., Fenno, L.E., Davidson, T.J., Mogri, M. & Deisseroth, K. Optogenetics in neural systems. Neuron 71, 9–34 (2011).

    Article  CAS  Google Scholar 

  27. Witter, M.P. The perforant path: projections from the entorhinal cortex to the dentate gyrus. Prog. Brain Res. 163, 43–61 (2007).

    Article  Google Scholar 

  28. Berger, T.K., Silberberg, G., Perin, R. & Markram, H. Brief bursts self-inhibit and correlate the pyramidal network. PLoS Biol. 8, e1000473 (2010).

    Article  Google Scholar 

  29. Kapfer, C., Glickfeld, L.L., Atallah, B.V. & Scanziani, M. Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex. Nat. Neurosci. 10, 743–753 (2007).

    Article  CAS  Google Scholar 

  30. Bonnevie, T. et al. Grid cells require excitatory drive from the hippocampus. Nat. Neurosci. doi:10.1038/nn.3311 (20 January 2013).

  31. Burgess, N., Barry, C. & O′Keefe, J. An oscillatory interference model of grid cell firing. Hippocampus 17, 801–812 (2007).

    Article  Google Scholar 

  32. Kropff, E. & Treves, A. The emergence of grid cells: intelligent design or just adaptation? Hippocampus 18, 1256–1269 (2008).

    Article  Google Scholar 

  33. Zilli, E.A. & Hasselmo, M.E. Coupled noisy spiking neurons as velocity-controlled oscillators in a model of grid cell spatial firing. J. Neurosci. 30, 13850–13860 (2010).

    Article  CAS  Google Scholar 

  34. Amari, S. Dynamics of pattern formation in lateral-inhibition type neural fields. Biol. Cybern. 27, 77–87 (1977).

    Article  CAS  Google Scholar 

  35. Zhang, K. Representation of spatial orientation by the intrinsic dynamics of the head-direction cell ensemble: a theory. J. Neurosci. 16, 2112–2126 (1996).

    Article  CAS  Google Scholar 

  36. Song, P. & Wang, X.J. Angular path integration by moving “hill of activity”: a spiking neuron model without recurrent excitation of the head-direction system. J. Neurosci. 25, 1002–1014 (2005).

    Article  CAS  Google Scholar 

  37. Boucheny, C., Brunel, N. & Arleo, A. A continuous attractor network model without recurrent excitation: maintenance and integration in the head direction cell system. J. Comput. Neurosci. 18, 205–227 (2005).

    Article  Google Scholar 

  38. Kang, K., Shelley, M. & Sompolinsky, H. Mexican hats and pinwheels in visual cortex. Proc. Natl. Acad. Sci. USA 100, 2848–2853 (2003).

    Article  CAS  Google Scholar 

  39. Ben-Yishai, R., Bar-Or, R.L. & Sompolinsky, H. Theory of orientation tuning in visual cortex. Proc. Natl. Acad. Sci. USA 92, 3844–3848 (1995).

    Article  CAS  Google Scholar 

  40. Compte, A., Brunel, N., Goldman-Rakic, P.S. & Wang, X.J. Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model. Cereb. Cortex 10, 910–923 (2000).

    Article  CAS  Google Scholar 

  41. Kloosterman, F., Van Haeften, T., Witter, M.P. & Lopes Da Silva, F.H. Electrophysiological characterization of interlaminar entorhinal connections: an essential link for re-entrance in the hippocampal-entorhinal system. Eur. J. Neurosci. 18, 3037–3052 (2003).

    Article  Google Scholar 

  42. Van Haeften, T., Baks-Te-Bulte, L., Goede, P.H., Wouterlood, F.G. & Witter, M.P. Morphological and numerical analysis of synaptic interactions between neurons in deep and superficial layers of the entorhinal cortex of the rat. Hippocampus 13, 943–952 (2003).

    Article  Google Scholar 

  43. Morgan, R.J., Santhakumar, V. & Soltesz, I. Modeling the dentate gyrus. Prog. Brain Res. 163, 639–658 (2007).

    Article  Google Scholar 

  44. Acsady, L., Kamondi, A., Sik, A., Freund, T. & Buzsaki, G. GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus. J. Neurosci. 18, 3386–3403 (1998).

    Article  CAS  Google Scholar 

  45. Danglot, L., Triller, A. & Marty, S. The development of hippocampal interneurons in rodents. Hippocampus 16, 1032–1060 (2006).

    Article  CAS  Google Scholar 

  46. Berger, T.K., Perin, R., Silberberg, G. & Markram, H. Frequency-dependent disynaptic inhibition in the pyramidal network: a ubiquitous pathway in the developing rat neocortex. J. Physiol. (Lond.) 587, 5411–5425 (2009).

    Article  CAS  Google Scholar 

  47. Paxinos, G. & Watson, C. The Rat Brain In Stereotaxic Coordinates (Academic Press, San Diego, 1998).

  48. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

    Article  CAS  Google Scholar 

  49. Shaner, N.C. et al. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat. Biotechnol. 22, 1567–1572 (2004).

    Article  CAS  Google Scholar 

  50. Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Deisseroth (Stanford University) for providing the ChR2(H134R) plasmid, I.E.J. Assebø for histological reconstructions, P. Girão for programming and A. Treves for comments on the manuscript. This work was supported by the Kavli Foundation, an EU 7th framework grant ('Spacebrain' grant agreement 200873), and Centre of Excellence (145993), equipment (181676) and research (191929) grants from the Norwegian Research Council, and an Advanced Investigator Grant from the European Research Council ('CIRCUIT', grant 232608).

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Contributions

J.J.C. and M.P.W. designed the experiments. All experiments were carried out by J.J.C. with the help of R.C., who performed the stereotaxic viral injections and post-hoc immunohistochemistry, and K.Z., who helped with the cluster recordings. J.J.C., R.C. and K.Z. performed experimental analyses. A.W., B.D. and Y.R. did the network simulations. S.-J.Z. and J.Y. designed and provided the rAAV. J.J.C., A.W., Y.R., E.I.M. and M.P.W. wrote the manuscript, and all authors contributed to discussion and interpretation of results.

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Correspondence to Yasser Roudi or Menno P Witter.

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Couey, J., Witoelar, A., Zhang, SJ. et al. Recurrent inhibitory circuitry as a mechanism for grid formation. Nat Neurosci 16, 318–324 (2013). https://doi.org/10.1038/nn.3310

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