Dynamic-Clamp pp 199-215 | Cite as

Using “Hard” Real-Time Dynamic Clamp to Study Cellular and Network Mechanisms of Synchronization in the Hippocampal Formation

  • John A. White
  • Fernando R. Fernandez
  • Michael N. Economo
  • Tilman J. Kispersky
Part of the Springer Series in Computational Neuroscience book series (NEUROSCI, volume 1)


We report on development and use of dynamic-clamp technology to understand how synchronous neuronal activity is generated in the hippocampus and entorhinal cortex. We find that “hard” real-time dynamic-clamp systems, characterized by very small maximal errors in timing of feedback, are necessary for cases in which fast voltage-gated channels are being mimicked in experiments. Using a hard real-time system to study cellular oscillations in entorhinal cortex, we demonstrate that the stochastic gating of persistent Na+ channels is necessary for cellular oscillations, and that cellular oscillations lead to dynamic changes in gain for conductance-based synaptic inputs. At the network level, we review experiments demonstrating that oscillating entorhinal stellate cells synchronize best via mutually excitatory interactions. Next, we show that cellular oscillations are volatile in the hypothesized “high-conductance” state, thought to occur in vivo, and suggest alternate means by which coherent activity can be generated in the absence of strong cellular oscillations. We close by discussing future developments that will increase the utility and widespread use of the dynamic-clamp method.


Stellate Cell Entorhinal Cortex Synaptic Input Theta Rhythm Decay Time Constant 



We thank past and present students and collaborators on dynamic-clamp work, including M.I. Banks, J.C. Bettencourt, M. Binder, R.J. Butera, D.J. Christini, A.D. Dorval, E. Idoux, K.P. Lillis, N. Kopell, L.E. Moore, T.I. Netoff, P. Randeria , and L. Stupin. This work was supported by grants from the National Institutes of Health (NCRR, NIMH, and NINDS).


  1. Acker CD, Kopell N, White JA (2003) Synchronization of strongly coupled excitatory neurons: relating network behavior to biophysics. J Comput Neurosci 15:71–90.PubMedCrossRefGoogle Scholar
  2. Alonso A, Llinas RR (1989) Subthreshold Na+-dependent theta-like rhythmicity in stellate cells of entorhinal cortex layer II. Nature 342:175–177.PubMedCrossRefGoogle Scholar
  3. Alonso A, Klink R (1993) Differential electroresponsiveness of stellate and pyramidal-like cells of medial entorhinal cortex layer II. J Neurophysiol 70:128–143.PubMedGoogle Scholar
  4. Banks MI, Li TB, Pearce RA (1998) The synaptic basis of GABAA,slow. J Neurosci 18:1305–1317.PubMedGoogle Scholar
  5. Bettencourt JC, Lillis KP, Stupin LR, White JA (2008) Effects of imperfect dynamic clamp: Computational and experimental results. J Neurosci Methods 169:282–289.PubMedCrossRefGoogle Scholar
  6. Bland BH, Colom LV (1993) Extrinsic and intrinsic properties underlying oscillation and synchrony in limbic cortex. Prog Neurobiol 41:157–208.PubMedCrossRefGoogle Scholar
  7. Borg-Graham LJ, Monier C, Fregnac Y (1998) Visual input evokes transient and strong shunting inhibition in visual cortical neurons. Nature 393:369–373.PubMedCrossRefGoogle Scholar
  8. Burgess N, Barry C, O’Keefe J (2007) An oscillatory interference model of grid cell firing. Hippocampus 17:801–812.PubMedCrossRefGoogle Scholar
  9. Butera RJ, Jr., Wilson CG, Delnegro CA, Smith JC (2001) A methodology for achieving high-speed rates for artificial conductance injection in electrically excitable biological cells. IEEE Trans Biomed Eng 48:1460–1470.PubMedCrossRefGoogle Scholar
  10. Buzsáki G (2002) Theta oscillations in the hippocampus. Neuron 33:325–340.PubMedCrossRefGoogle Scholar
  11. Canavier CC, Butera RJ, Dror RO, Baxter DA, Clark JW, Byrne JH (1997) Phase response characteristics of model neurons determine which patterns are expressed in a ring circuit model of gait generation. Biol Cybern 77:367–380.PubMedCrossRefGoogle Scholar
  12. Chow CC, White JA, Ritt J, Kopell N (1998) Frequency control in synchronized networks of inhibitory neurons. J Comput Neurosci 5:407–420.PubMedCrossRefGoogle Scholar
  13. Christini DJ, Stein KM, Markowitz SM, Lerman BB (1999) Practical real-time computing system for biomedical experiment interface. Ann Biomed Eng 27:180–186.PubMedCrossRefGoogle Scholar
  14. Destexhe A, Pare D (1999) Impact of network activity on the integrative properties of neocortical pyramidal neurons in vivo. J Neurophysiol 81:1531–1547.PubMedGoogle Scholar
  15. Destexhe A, Rudolph M, Pare D (2003) The high-conductance state of neocortical neurons in vivo. Nat Rev Neurosci 4:739–751.PubMedCrossRefGoogle Scholar
  16. Dickson CT, Magistretti J, Shalinsky MH, Fransen E, Hasselmo ME, Alonso A (2000) Properties and role of I(h) in the pacing of subthreshold oscillations in entorhinal cortex layer II neurons. J Neurophysiol 83:2562–2579.PubMedGoogle Scholar
  17. Dorval AD, White JA (2005) Channel noise is essential for perithreshold oscillations in entorhinal stellate neurons. J Neurosci 25:10025–10028.PubMedCrossRefGoogle Scholar
  18. Dorval AD, White JA (2006) Synaptic input statistics tune the variability and reproducibility of neuronal responses. Chaos 16:026105.PubMedCrossRefGoogle Scholar
  19. Dorval AD, Christini DJ, White JA (2001) Real-time Linux dynamic clamp: a fast and flexible way to construct virtual ion channels in living cells. Ann Biomed Eng 29:897–907.PubMedCrossRefGoogle Scholar
  20. Erchova I, Kreck G, Heinemann U, Herz AV (2004) Dynamics of rat entorhinal cortex layer II and III cells: characteristics of membrane potential resonance at rest predict oscillation properties near threshold. J Physiol 560:89–110.PubMedCrossRefGoogle Scholar
  21. Ermentrout B, Kopell N (1991) Multiple pulse interactions and averaging in systems of coupled oscillators. J Math Biol 29:195–217.CrossRefGoogle Scholar
  22. Fernandez FR, White JA (2008) Artificial synaptic conductances reduce subthreshold oscillations and periodic firing in stellate cells of the entorhinal cortex. J Neurosci 28:3790–3803.PubMedCrossRefGoogle Scholar
  23. Fransen E, Alonso AA, Dickson CT, Magistretti J, Hasselmo ME (2004) Ionic mechanisms in the generation of subthreshold oscillations and action potential clustering in entorhinal layer II stellate neurons. Hippocampus 14:368–384.PubMedCrossRefGoogle Scholar
  24. Gillies MJ, Traub RD, LeBeau FE, Davies CH, Gloveli T, Buhl EH, Whittington MA (2002) A model of atropine-resistant theta oscillations in rat hippocampal area CA1. J Physiol 543:779–793.PubMedCrossRefGoogle Scholar
  25. Giocomo LM, Zilli EA, Fransen E, Hasselmo ME (2007) Temporal frequency of subthreshold oscillations scales with entorhinal grid cell field spacing. Science 315:1719–1722.PubMedCrossRefGoogle Scholar
  26. Gloor P (1997) The temporal lobe and limbic system. New York: Oxford University Press.Google Scholar
  27. Gloveli T, Dugladze T, Saha S, Monyer H, Heinemann U, Traub RD, Whittington MA, Buhl EH (2005a) Differential involvement of oriens/pyramidale interneurones in hippocampal network oscillations in vitro. J Physiol 562:131–147.Google Scholar
  28. Gloveli T, Dugladze T, Rotstein HG, Traub RD, Monyer H, Heinemann U, Whittington MA, Kopell NJ (2005b) Orthogonal arrangement of rhythm-generating microcircuits in the hippocampus. Proc Natl Acad Sci USA 102:13295–13300.Google Scholar
  29. Haas JS, White JA (2002) Frequency selectivity of layer II stellate cells in the medial entorhinal cortex. J Neurophysiol 88:2422–2429.PubMedCrossRefGoogle Scholar
  30. Haas JS, Dorval AD, II, White JA (2007) Contributions of Ih to feature selectivity in layer II stellate cells of the entorhinal cortex. J Comput Neurosci 22:161–171.PubMedCrossRefGoogle Scholar
  31. Hansel D, Mato G, Meunier C (1995) Synchrony in excitatory neural networks. Neural Comput 7:307–337.PubMedCrossRefGoogle Scholar
  32. Hasselmo ME, Giocomo LM, Zilli EA (2007) Grid cell firing may arise from interference of theta frequency membrane potential oscillations in single neurons. Hippocampus 17:1252–1271.PubMedCrossRefGoogle Scholar
  33. Hille B (2001) Ion channels of excitable membranes, 3rd Edition. Sunderland, Mass.: Sinauer.Google Scholar
  34. Hughes SW, Lorincz M, Cope DW, Crunelli V (2008) NeuReal: An interactive simulation system for implementing artificial dendrites and large hybrid networks. J Neurosci Methods 169:290–301.PubMedCrossRefGoogle Scholar
  35. Kispersky TJ, White JA (2008) Stochastic models of ion channel gating. Scholarpedia 3:1327.CrossRefGoogle Scholar
  36. Klink R, Alonso A (1993) Ionic mechanisms for the subthreshold oscillations and differential electroresponsiveness of medial entorhinal cortex layer II neurons. J Neurophysiol 70:144–157.PubMedGoogle Scholar
  37. Kullmann PH, Wheeler DW, Beacom J, Horn JP (2004) Implementation of a fast 16-Bit dynamic clamp using LabVIEW-RT. J Neurophysiol 91:542–554.PubMedCrossRefGoogle Scholar
  38. Maccaferri G, Roberts JD, Szucs P, Cottingham CA, Somogyi P (2000) Cell surface domain specific postsynaptic currents evoked by identified GABAergic neurones in rat hippocampus in vitro. J Physiol 524 Pt 1:91–116.Google Scholar
  39. Milescu LS, Yamanishi T, Ptak K, Mogri MZ, Smith JC (2008) Real-time kinetic modeling of voltage-gated ion channels using dynamic clamp. Biophys J 95:66–87.Google Scholar
  40. Netoff TI, Acker CD, Bettencourt JC, White JA (2005a) Beyond two-cell networks: experimental measurement of neuronal responses to multiple synaptic inputs. J Comput Neurosci 18:287–295.Google Scholar
  41. Netoff TI, Banks MI, Dorval AD, Acker CD, Haas JS, Kopell N, White JA (2005b) Synchronization in hybrid neuronal networks of the hippocampal formation. J Neurophysiol 93:1197–1208.Google Scholar
  42. O'Keefe J (1993) Hippocampus, theta, and spatial memory. Curr Opin Neurobiol 3:917–924.PubMedCrossRefGoogle Scholar
  43. O’Keefe J, Burgess N (2005) Dual phase and rate coding in hippocampal place cells: theoretical significance and relationship to entorhinal grid cells. Hippocampus 15:853–866.PubMedCrossRefGoogle Scholar
  44. Pike FG, Goddard RS, Suckling JM, Ganter P, Kasthuri N, Paulsen O (2000) Distinct frequency preferences of different types of rat hippocampal neurones in response to oscillatory input currents. J Physiol 529 Pt 1:205–213.Google Scholar
  45. Pinto RD, Elson RC, Szucs A, Rabinovich MI, Selverston AI, Abarbanel HD (2001) Extended dynamic clamp: controlling up to four neurons using a single desktop computer and interface. J Neurosci Methods 108:39–48.PubMedCrossRefGoogle Scholar
  46. Robinson HP, Kawai N (1993) Injection of digitally synthesized synaptic conductance transients to measure the integrative properties of neurons. J Neurosci Meth 49:157–165.CrossRefGoogle Scholar
  47. Rotstein HG, Pervouchine DD, Acker CD, Gillies MJ, White JA, Buhl EH, Whittington MA, Kopell N (2005) Slow and fast inhibition and an H-current interact to create a theta rhythm in a model of CA1 interneuron network. J Neurophysiol 94:1509–1518.PubMedCrossRefGoogle Scholar
  48. Schreiber S, Erchova I, Heinemann U, Herz AV (2004) Subthreshold resonance explains the frequency-dependent integration of periodic as well as random stimuli in the entorhinal cortex. J Neurophysiol 92:408–415.PubMedCrossRefGoogle Scholar
  49. Sharp AA, O’Neil MB, Abbott LF, Marder E (1993) Dynamic clamp: Computer-generated conductances in real neurons. J Neurophysiol 69:992–995.PubMedGoogle Scholar
  50. Shoham S, O'Connor DH, Sarkisov DV, Wang SS (2005) Rapid neurotransmitter uncaging in spatially defined patterns. Nat Methods 2:837–843.PubMedCrossRefGoogle Scholar
  51. Sohal VS, Huguenard JR (2005) Inhibitory coupling specifically generates emergent gamma oscillations in diverse cell types. Proc Natl Acad Sci USA 102:18638–18643.PubMedCrossRefGoogle Scholar
  52. Vida I, Bartos M, Jonas P (2006) Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates. Neuron 49:107–117.PubMedCrossRefGoogle Scholar
  53. Wang XJ, Buzsáki G (1996) Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. J Neurosci 16:6402–6413.PubMedGoogle Scholar
  54. White JA, Budde T, Kay AR (1995) A bifurcation analysis of neuronal subthreshold oscillations. Biophys J 69:1203–1217.PubMedCrossRefGoogle Scholar
  55. White JA, Klink R, Alonso A, Kay AR (1998a) Noise from voltage-gated ion channels may influence neuronal dynamics in the entorhinal cortex. J Neurophysiol 80:262–269.Google Scholar
  56. White JA, Chow CC, Ritt J, Soto-Trevino C, Kopell N (1998b) Synchronization and oscillatory dynamics in heterogeneous, mutually inhibited neurons. J Comput Neurosci 5:5–16.Google Scholar
  57. White JA, Rubinstein JT, Kay AR (2000a) Channel noise in neurons. Trends Neurosci 23:131–137.Google Scholar
  58. White JA, Banks MI, Pearce RA, Kopell NJ (2000b) Networks of interneurons with fast and slow gamma-aminobutyric acid type A (GABAA) kinetics provide substrate for mixed gamma-theta rhythm. Proc Natl Acad Sci USA 97:8128–8133.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • John A. White
    • 1
  • Fernando R. Fernandez
  • Michael N. Economo
  • Tilman J. Kispersky
  1. 1.Department of Bioengineering, Brain InstituteUniversity of UtahSalt Lake CityUSA

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