Ephaptic coupling of cortical neurons


The electrochemical processes that underlie neural function manifest themselves in ceaseless spatiotemporal field fluctuations. However, extracellular fields feed back onto the electric potential across the neuronal membrane via ephaptic coupling, independent of synapses. The extent to which such ephaptic coupling alters the functioning of neurons under physiological conditions remains unclear. To address this question, we stimulated and recorded from rat cortical pyramidal neurons in slices with a 12-electrode setup. We found that extracellular fields induced ephaptically mediated changes in the somatic membrane potential that were less than 0.5 mV under subthreshold conditions. Despite their small size, these fields could strongly entrain action potentials, particularly for slow (<8 Hz) fluctuations of the extracellular field. Finally, we simultaneously measured from up to four patched neurons located proximally to each other. Our findings indicate that endogenous brain activity can causally affect neural function through field effects under physiological conditions.

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Figure 1: Simultaneous recordings from up to 12 electrodes inside and outside a single neuron in rat slice during intra- and extracellular stimulation.
Figure 2: Subthreshold extracellular field entrainment.
Figure 3: Weak electric fields entrain spiking activity of individual neurons.
Figure 4: Ephaptic coupling leads to coordinated spiking activity among nearby neurons.


  1. 1

    Koch, C. Biophysics of Computation (Oxford University Press, 1999).

  2. 2

    Stuart, G., Spruston, N. & Hausser, M. Dendrites (Oxford University Press, 2008).

  3. 3

    Haider, B. & McCormick, D.A. Rapid neocortical dynamics: cellular and network mechanisms. Neuron 62, 171–189 (2009).

    CAS  Article  Google Scholar 

  4. 4

    Gold, C., Henze, D.A., Koch, C. & Buzsáki, G. On the origin of the extracellular action potential waveform: a modeling study. J. Neurophysiol. 95, 3113–3128 (2006).

    CAS  Article  Google Scholar 

  5. 5

    Pettersen, K.H. & Einevoll, G.T. Amplitude variability and extracellular low-pass filtering of neuronal spikes. Biophys. J. 94, 784–802 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Steriade, M., Nunez, A. & Amzica, F. A novel slow (&lt; 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J. Neurosci. 13, 3252–3265 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Steriade, M., Nunez, A. & Amzica, F. Intracellular analysis of relations between the slow (&lt;1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. J. Neurosci. 13, 3266–3283 (1993).

    CAS  Article  Google Scholar 

  8. 8

    Vanderwolf, C.H. Hippocampal electrical activity and voluntary movement in the rat. Electroencephalogr. Clin. Neurophysiol. 26, 407–418 (1969).

    CAS  Article  Google Scholar 

  9. 9

    Buzsáki, G., Leung, L.W. & Vanderwolf, C.H. Cellular bases of hippocampal EEG in the behaving rat. Brain Res. 287, 139–171 (1983).

    Article  Google Scholar 

  10. 10

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

    Article  Google Scholar 

  11. 11

    Lubenov, E.V. & Siapas, A.G. Hippocampal theta oscillations are travelling waves. Nature 459, 534–539 (2009).

    CAS  Article  Google Scholar 

  12. 12

    Buzsáki, G., Horvath, Z., Urioste, R., Hetke, J. & Wise, K. High-frequency network oscillation in the hippocampus. Science 256, 1025–1027 (1992).

    Article  Google Scholar 

  13. 13

    Ylinen, A. et al. Sharp wave–associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms. J. Neurosci. 15, 30–46 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Arvanitaki, A. Effects evoked in an axon by the activity of a contiguous one. J. Neurophysiol. 5, 89–108 (1942).

    Article  Google Scholar 

  15. 15

    Traub, R.D., Dudek, F.E., Taylor, C.P. & Knowles, W.D. Simulation of hippocampal afterdischarges synchronized by electrical interactions. Neuroscience 14, 1033–1038 (1985).

    CAS  Article  Google Scholar 

  16. 16

    Chan, C.Y. & Nicholson, C. Modulation by applied electric fields of Purkinje and stellate cell activity in the isolated turtle cerebellum. J. Physiol. (Lond.) 371, 89–114 (1986).

    CAS  Article  Google Scholar 

  17. 17

    Jefferys, J.G. Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions. Physiol. Rev. 75, 689–723 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Radman, T., Su, Y., An, J.H., Parra, L.C. & Bikson, M. Spike timing amplifies the effect of electric fields on neurons: implications for endogenous field effects. J. Neurosci. 27, 3030–3036 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Deans, J.K., Powell, A.D. & Jefferys, J.G. Sensitivity of coherent oscillations in rat hippocampus to AC electric fields. J. Physiol. 583, 555–565 (2007).

    CAS  Article  Google Scholar 

  20. 20

    Anastassiou, C.A., Montgomery, S.M., Barahona, M., Buzsáki, G. & Koch, C. The effect of spatially inhomogeneous extracellular electric fields on neurons. J. Neurosci. 30, 1925–1936 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Chan, C.Y., Hounsgaard, J. & Nicholson, C. Effects of electric fields on transmembrane potential and excitability of turtle cerebellar Purkinje cells in vitro. J. Physiol. (Lond.) 402, 751–771 (1988).

    CAS  Article  Google Scholar 

  22. 22

    Ozen, S. et al. Transcranial electric stimulation entrains cortical neuronal populations in rats. J. Neurosci. 30, 11476–11485 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Noebels, J.L. & Prince, D.A. Development of focal seizures in cerebral cortex: role of axon terminal bursting. J. Neurophysiol. 41, 1267–1281 (1978).

    CAS  Article  Google Scholar 

  24. 24

    Jefferys, J.G. & Haas, H.L. Synchronized bursting of CA1 hippocampal pyramidal cells in the absence of synaptic transmission. Nature 300, 448–450 (1982).

    CAS  Article  Google Scholar 

  25. 25

    Ghai, R.S., Bikson, M. & Durand, D.M. Effects of applied electric fields on low-calcium epileptiform activity in the CA1 region of rat hippocampal slices. J. Neurophysiol. 84, 274–280 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Marshall, L., Helgadottir, H., Molle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006).

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

    Fries, P., Reynolds, J.H., Rorie, A.E. & Desimone, R. Modulation of oscillatory neuronal synchronization by selective visual attention. Science 291, 1560–1563 (2001).

    CAS  Article  Google Scholar 

  29. 29

    Womelsdorf, T., Fries, P., Mitra, P.P. & Desimone, R. Gamma-band synchronization in visual cortex predicts speed of change detection. Nature 439, 733–736 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Womelsdorf, T. et al. Modulation of neuronal interactions through neuronal synchronization. Science 316, 1609–1612 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Colgin, L.L. et al. Frequency of gamma oscillations routes flow of information in the hippocampus. Nature 462, 353–357 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Rutishauser, U., Ross, I.B., Mamelak, A.N. & Schuman, E.M. Human memory strength is predicted by theta-frequency phase-locking of single neurons. Nature 464, 903–907 (2010).

    CAS  Article  Google Scholar 

  33. 33

    Kamondi, A., Acsady, L., Wang, X.J. & Buzsáki, G. Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo: activity-dependent phase-precession of action potentials. Hippocampus 8, 244–261 (1998).

    CAS  Article  Google Scholar 

  34. 34

    Weiss, S.A. & Faber, D.S. Field effects in the CNS play functional roles. Front Neural Circuits 4, 15 (2010).

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Mann, E.O. & Paulsen, O. Local field potential oscillations as a cortical soliloquy. Neuron 67, 3–5 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Pastalkova, E., Itskov, V., Amarasingham, A. & Buzsáki, G. Internally generated cell assembly sequences in the rat hippocampus. Science 321, 1322–1327 (2008).

    CAS  Article  Google Scholar 

  37. 37

    Kreiman, G. et al. Object selectivity of local field potentials and spikes in the macaque inferior temporal cortex. Neuron 49, 433–445 (2006).

    CAS  Article  Google Scholar 

  38. 38

    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).

    CAS  Article  Google Scholar 

  39. 39

    Kreiman, G., Koch, C. & Fried, I. Category-specific visual responses of single neurons in the human medial temporal lobe. Nat. Neurosci. 3, 946–953 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Quiroga, R.Q., Reddy, L., Kreiman, G., Koch, C. & Fried, I. Invariant visual representation by single neurons in the human brain. Nature 435, 1102–1107 (2005).

    CAS  Article  Google Scholar 

  41. 41

    Logothetis, N.K., Kayser, C. & Oeltermann, A. In vivo measurement of cortical impedance spectrum in monkeys: implications for signal propagation. Neuron 55, 809–823 (2007).

    CAS  Article  Google Scholar 

  42. 42

    Montoro, R.J. & Yuste, R. Gap junctions in developing neocortex: a review. Brain Res. Brain Res. Rev. 47, 216–226 (2004).

    CAS  Article  Google Scholar 

  43. 43

    Histed, M.H., Bonin, V. & Reid, R.C. Direct activation of sparse, distributed populations of cortical neurons by electrical microstimulation. Neuron 63, 508–522 (2009).

    CAS  Article  Google Scholar 

  44. 44

    Milstein, J., Mormann, F., Fried, I. & Koch, C. Neuronal shot noise and Brownian 1/f2 behavior in the local field potential. PLoS ONE 4, e4338 (2009).

    Article  Google Scholar 

  45. 45

    Holt, G.R. & Koch, C. Electrical interactions via the extracellular potential near cell bodies. J. Comput. Neurosci. 6, 169–184 (1999).

    CAS  Article  Google Scholar 

  46. 46

    Jacobson, G.A. et al. Subthreshold voltage noise of rat neocortical pyramidal neurones. J. Physiol. 564, 145–160 (2005).

    CAS  Article  Google Scholar 

  47. 47

    Hutcheon, B. & Yarom, Y. Resonance, oscillation and the intrinsic frequency preferences of neurons. Trends Neurosci 23, 216–222 (2000).

    CAS  Article  Google Scholar 

  48. 48

    Kayser, C., Montemurro, M.A., Logothetis, N.K. & Panzeri, S. Spike-phase coding boosts and stabilizes information carried by spatial and temporal spike patterns. Neuron 61, 597–608 (2009).

    CAS  Article  Google Scholar 

  49. 49

    Tabareau, N., Slotine, J.J. & Pham, Q.C. How synchronization protects from noise. PLOS Comput. Biol. 6, e1000637 (2010).

    Article  Google Scholar 

  50. 50

    Berens, P. CircStat: a MATLAB toolbox for circular statistics. J. Stat. Softw. 31, 1–21 (2009).

    Article  Google Scholar 

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We thank G. Buzsáki, U. Rutishauser and E. Schomburg for comments and discussions and J. Bastiaansen for assistance. This work was funded by the Engineering Physical Sciences Research Council (C.A.A.), the Sloan-Swartz Foundation (C.A.A.), the Swiss National Science Foundation (C.A.A.), EU Synapse (R.P.), the National Science Foundation (C.K. and C.A.A.), the Mathers Foundation (C.K. and C.A.A.) and the World Class University program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R31-10008, C.K.).

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C.A.A. and C.K. designed the experiments. C.A.A. and R.P. performed the experiments. C.A.A. wrote the codes and analyzed the data. C.A.A., R.P., H.M. and C.K. wrote the manuscript.

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Correspondence to Costas A Anastassiou.

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The authors declare no competing financial interests.

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Anastassiou, C., Perin, R., Markram, H. et al. Ephaptic coupling of cortical neurons. Nat Neurosci 14, 217–223 (2011). https://doi.org/10.1038/nn.2727

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