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The action potential in mammalian central neurons

Key Points

  • Neuronal cell bodies in the mammalian CNS typically have more than a dozen distinct voltage-dependent conductances. The greater number of conductances compared to the squid axon is associated with much more complex firing patterns than can be produced by the squid axon.

  • Action potential shapes and firing patterns differ widely among different types of neurons.

  • One recognizable phenotype is that of fast-spiking neurons, which are capable of firing steadily at high frequencies and have narrow action potentials. This phenotype is typical of many interneurons and is associated with the expression of Kv3 family potassium channels.

  • Some neurons with fast-spiking behaviour express resurgent sodium current, a component of tetrodotoxin-sensitive current that flows after the spike and promotes high-frequency firing.

  • Most neurons have large calcium currents carried by multiple types of calcium channels. The calcium current is largest during the falling phase of the action potential but is often outweighed by calcium-activated potassium current, activated by extremely rapid coupling to calcium entry.

  • Potassium channels commonly playing a major part in the repolarization of action potentials include Kv3 channels, IA (Kv4) channels, ID (Kv1) channels and large conductance calcium-activated potassium (BK) channels.

  • Inactivation of potassium currents can produce frequency-dependent broadening of the action potential, which can produce synaptic facilitation. Potassium channels whose inactivation can lead to frequency-dependent spike broadening include BK channels and inactivating Kv1 family channels located in presynaptic terminals.

  • Following the spike, many neurons have afterpotentials, including multiple types of afterhyperpolarizations with time courses lasting up to several seconds. Pyramidal neurons often have a prominent afterdepolarization which, if large enough, can lead to all-or-none bursting.

  • Currents active at subthreshold voltages can greatly influence firing patterns and frequency. These include IA and ID potassium currents, steady-state “persistent” sodium current, T-type calcium current, and the hyperpolarization-activated cation current called Ih.

  • The system of ionic currents that controls action potential shape and firing patterns in central neurons, although complex, has remarkable advantages for pursuing general problems in systems biology (such as robustness and redundancy): it has highly quantifiable elements, which are well-suited to mathematical modelling.

Abstract

The action potential of the squid giant axon is formed by just two voltage-dependent conductances in the cell membrane, yet mammalian central neurons typically express more than a dozen different types of voltage-dependent ion channels. This rich repertoire of channels allows neurons to encode information by generating action potentials with a wide range of shapes, frequencies and patterns. Recent work offers an increasingly detailed understanding of how the expression of particular channel types underlies the remarkably diverse firing behaviour of various types of neurons.

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Figure 1: Diversity of action potentials in central neurons.
Figure 2: Phase-plane plots and action potential clamp.
Figure 3: Sodium, calcium, and calcium-activated potassium currents during action potentials.
Figure 4: Role of Kv3 potassium currents in fast-spiking neurons.
Figure 5: Frequency-dependent spike broadening from inactivation of potassium current.
Figure 6: Afterhyperpolarizations, afterdepolarizations, and all-or-none burst firing.

References

  1. 1

    Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Hille, B. Ion Channels of Excitable Membranes (Sinauer, Sunderland, 2001).

    Google Scholar 

  3. 3

    Llinás, R. R. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science 242, 1654–1664 (1988). Seminal review/manifesto by a pioneer of CNS cellular electrophysiology, surveying the wide variety of intrinsic excitability of central neurons and emphasizing the intrinsic oscillatory behaviour of cells and circuits.

    PubMed  PubMed Central  Google Scholar 

  4. 4

    Guttman, R. & Barnhill, R. Oscillation and repetitive firing in squid axons. Comparison of experiments with computations. J. Gen. Physiol. 55, 104–118 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Connors, B. W. & Gutnick, M. J. Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci. 13, 99–104 (1990).

    CAS  PubMed  Google Scholar 

  6. 6

    Erisir, A., Lau, D., Rudy, B. & Leonard, C. S. Function of specific K+ channels in sustained high-frequency firing of fast-spiking neocortical interneurons. J. Neurophysiol. 82, 2476–2489 (1999).

    CAS  PubMed  Google Scholar 

  7. 7

    Bevan, M. D. & Wilson, C. J. Mechanisms underlying spontaneous oscillation and rhythmic firing in rat subthalamic neurons. J. Neurosci. 19, 7617–7628 (1999).

    CAS  PubMed  Google Scholar 

  8. 8

    Nowak, L. G., Azouz, R., Sanchez-Vives, M. V., Gray, C. M. & McCormick, D. A. Electrophysiological classes of cat primary visual cortical neurons in vivo as revealed by quantitative analyses. J. Neurophysiol. 89, 1541–1566 (2003).

    PubMed  Google Scholar 

  9. 9

    Tateno, T., Harsch, A. & Robinson, H. P. Threshold firing frequency-current relationships of neurons in rat somatosensory cortex: type 1 and type 2 dynamics. J. Neurophysiol. 92, 2283–2294 (2004).

    CAS  PubMed  Google Scholar 

  10. 10

    Forti, L., Cesana, E., Mapelli, J. & D'Angelo, E. Ionic mechanisms of autorhythmic firing in rat cerebellar Golgi cells. J. Physiol. 574, 711–729 (2006).

    CAS  PubMed  Google Scholar 

  11. 11

    Hodgkin, A. L. The local electric changes associated with repetitive action in a non-medullated axon. J. Physiol. 107, 165–181 (1948).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Connor, J. A. Neural repetitive firing: a comparative study of membrane properties of crustacean walking leg axons. J. Neurophysiol. 38, 922–332 (1975).

    CAS  PubMed  Google Scholar 

  13. 13

    Debanne, D. Information processing in the axon. Nature Rev. Neurosci. 5, 304–316 (2004).

    CAS  Google Scholar 

  14. 14

    Coetzee, W. A. et al. Molecular diversity of K+ channels. Ann. NY Acad. Sci. 868, 233–285 (1999).

    CAS  PubMed  Google Scholar 

  15. 15

    McCormick, D. A., Connors, B. W., Lighthall, J. W. & Prince, D. A. Comparative electrophysiology of pyramidal and sparsely spiny stellate neurons of the neocortex. J. Neurophysiol. 54, 782–806 (1985). Introduces 'regular-spiking', 'bursting' and 'fast-spiking' classifications of firing patterns of neocortical neurons, correlates firing patterns with spike shape, and identifies fast-spiking neocortical neurons as GABA-mediated interneurons.

    CAS  PubMed  Google Scholar 

  16. 16

    Kawaguchi, Y. Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex. J. Neurosci. 15, 2638–2655 (1995).

    CAS  Google Scholar 

  17. 17

    Mountcastle, V. B., Talbot, W. H., Sakata, H. & Hyvarinen, J. Cortical neuronal mechanisms in flutter-vibration studied in unanesthetized monkeys. Neuronal periodicity and frequency discrimination. J. Neurophysiol. 32, 452–484 (1969).

    CAS  PubMed  Google Scholar 

  18. 18

    Kawaguchi, Y. Physiological, morphological, and histochemical characterization of three classes of interneurons in rat neostriatum. J. Neurosci. 13, 4908–4923 (1993).

    CAS  PubMed  Google Scholar 

  19. 19

    Zhou, F. M. & Hablitz, J. J. Layer I neurons of rat neocortex. I. Action potential and repetitive firing properties. J. Neurophysiol. 76, 651–667 (1996).

    CAS  PubMed  Google Scholar 

  20. 20

    Descalzo, V. F., Nowak, L. G., Brumberg, J. C., McCormick, D. A. & Sanchez-Vives, M. V. Slow adaptation in fast-spiking neurons of visual cortex. J. Neurophysiol. 93, 1111–1118 (2005).

    CAS  PubMed  Google Scholar 

  21. 21

    Du, J., Zhang, L., Weiser, M., Rudy, B. & McBain, C. J. Developmental expression and functional characterization of the potassium-channel subunit Kv3.1b in parvalbumin-containing interneurons of the rat hippocampus. J. Neurosci. 16, 506–518 (1996).

    CAS  PubMed  Google Scholar 

  22. 22

    Massengill, J. L., Smith, M. A., Son, D. I. & O'Dowd, D. K. Differential expression of K4-AP currents and Kv3.1 potassium channel transcripts in cortical neurons that develop distinct firing phenotypes. J. Neurosci. 17, 3136–3147 (1997).

    CAS  PubMed  Google Scholar 

  23. 23

    Martina, M., Schultz, J. H., Ehmke, H., Monyer, H. & Jonas, P. Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. J. Neurosci. 18, 8111–8125 (1998).

    CAS  PubMed  Google Scholar 

  24. 24

    Lien, C. C., Martina, M., Schultz, J. H., Ehmke, H. & Jonas, P. Gating, modulation and subunit composition of voltage-gated K+ channels in dendritic inhibitory interneurones of rat hippocampus. J. Physiol. 538, 405–419 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Baranauskas, G., Tkatch, T., Nagata, K., Yeh, J. Z. & Surmeier, D. J. Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons. Nature Neurosci. 6, 258–266 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Lien, C. C. & Jonas, P. Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons. J. Neurosci. 23, 2058–2068 (2003). Uses the dynamic clamp technique to demonstrate that the Kv3-mediated potassium current speeds up firing and that deactivation kinetics are a crucial parameter for this effect.

    CAS  PubMed  Google Scholar 

  27. 27

    Rudy, B. & McBain, C. J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517–526 (2001). Comprehensive review of the correlation between the expression of Kv3 channels and the fast-spiking phenotype.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Southan, A. P. & Robertson, B. Electrophysiological characterization of voltage-gated K+ currents in cerebellar basket and purkinje cells: Kv1 and Kv3 channel subfamilies are present in basket cell nerve terminals. J. Neurosci. 20, 114–122 (2000).

    CAS  PubMed  Google Scholar 

  29. 29

    Martina, M., Yao, G. L. & Bean, B. P. Properties and functional role of voltage-dependent potassium channels in dendrites of rat cerebellar Purkinje neurons. J. Neurosci. 23, 5698–5707 (2003).

    CAS  PubMed  Google Scholar 

  30. 30

    McKay, B. E. & Turner, R. W. Kv3 K+ channels enable burst output in rat cerebellar Purkinje cells. Eur. J. Neurosci. 20, 729–739 (2004).

    CAS  Google Scholar 

  31. 31

    Martina, M., Metz, A. E. & Bean, B. P. Voltage-dependent potassium currents during fast spikes of rat cerebellar Purkinje neurons: inhibition by BDS-I toxin. J. Neurophysiol. 97, 563–571 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    Do, M. T. & Bean, B. P. Subthreshold sodium currents and pacemaking of subthalamic neurons: modulation by slow inactivation. Neuron 39, 109–120 (2003).

    CAS  PubMed  Google Scholar 

  33. 33

    Wigmore, M. A. & Lacey, M. G. A Kv3-like persistent, outwardly rectifying, Cs+-permeable, K+ current in rat subthalamic nucleus neurones. J. Physiol. 527, 493–506 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Brew, H. M. & Forsythe, I. D. Two voltage-dependent K+ conductances with complementary functions in postsynaptic integration at a central auditory synapse. J. Neurosci. 15, 8011–8022 (1995).

    CAS  PubMed  Google Scholar 

  35. 35

    Wang, L. Y., Gan, L., Forsythe, I. D. & Kaczmarek, L. K. Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones. J. Physiol. 509, 183–194 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Ishikawa, T. et al. Distinct roles of Kv1 and Kv3 potassium channels at the calyx of Held presynaptic terminal. J. Neurosci. 23, 10445–10453 (2003).

    CAS  PubMed  Google Scholar 

  37. 37

    Connors, B. W., Gutnick, M. J. & Prince, D. A. Electrophysiological properties of neocortical neurons in vitro. J. Neurophysiol. 48, 1302–1320 (1982). Classic description of all-or-none bursting, and of afterdepolarizations and action potential broadening, in neocortical pyramidal neurons.

    CAS  PubMed  Google Scholar 

  38. 38

    Staff, N. P., Jung, H. Y., Thiagarajan, T., Yao, M. & Spruston, N. Resting and active properties of pyramidal neurons in subiculum and CA1 of rat hippocampus. J. Neurophysiol. 84, 2398–2408 (2000).

    CAS  PubMed  Google Scholar 

  39. 39

    Geiger, J. R. & Jonas, P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28, 927–939 (2000). Remarkable sequence of current-clamp and voltage-clamp recordings from presynaptic terminals of mossy fibres and their postsynaptic targets, showing that presynaptic spikes are narrower than those in the cell body, that presynaptic spikes undergo frequency-dependent broadening due to inactivation of Kv1 family channels, and that spike broadening produces dramatic synaptic facilitation.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Coombs, J. S., Curtis, D. R. & Eccles, J. C. The interpretation of spike potentials of motoneurones. J. Physiol. 139, 198–231 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Grace, A. A. & Bunney, B. S. Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—2. Action potential generating mechanisms and morphological correlates. Neuroscience 10, 317–331 (1983).

    CAS  PubMed  Google Scholar 

  42. 42

    Hausser, M., Stuart, G., Racca, C. & Sakmann, B. Axonal initiation and active dendritic propagation of action potentials in substantia nigra neurons. Neuron 15, 637–647 (1995).

    CAS  PubMed  Google Scholar 

  43. 43

    Stuart, G., Schiller, J. & Sakmann, B. Action potential initiation and propagation in rat neocortical pyramidal neurons. J. Physiol. 505, 617–632 (1997). Uses double (and triple) patch pipette recordings in layer 5 pyramidal neurons to directly demonstrate that spikes are initiated in the axon before the soma — even with strong synaptic stimulation that first elicits regenerative potentials in dendrites. Also demonstrates back-propagation of axonal spikes into the dendritic tree.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Martina, M., Vida, I. & Jonas, P. Distal initiation and active propagation of action potentials in interneuron dendrites. Science 287, 295–300 (2000).

    CAS  PubMed  Google Scholar 

  45. 45

    Palmer, L. M. & Stuart, G. J. Site of action potential initiation in layer 5 pyramidal neurons. J. Neurosci. 26, 1854–1863 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Khaliq, Z. M. & Raman, I. M. Relative contributions of axonal and somatic Na channels to action potential initiation in cerebellar Purkinje neurons. J. Neurosci. 26, 1935–1944 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Shu, Y., Duque, A., Yu, Y., Haider, B. & McCormick, D. A. Properties of action-potential initiation in neocortical pyramidal cells: evidence from whole cell axon recordings. J. Neurophysiol. 97, 746–760 (2007).

    Google Scholar 

  48. 48

    Raman, I. M. & Bean, B. P. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J. Neurosci. 17, 4517–4526 (1997).

    CAS  Google Scholar 

  49. 49

    Kay, A. R. & Wong, R. K. Isolation of neurons suitable for patch-clamping from adult mammalian central nervous systems. J. Neurosci. Methods 16, 227–238 (1986).

    CAS  PubMed  Google Scholar 

  50. 50

    Mitterdorfer, J. & Bean, B. P. Potassium currents during the action potential of hippocampal CA3 neurons. J. Neurosci. 22, 10106–10115 (2002).

    CAS  PubMed  Google Scholar 

  51. 51

    Raman, I. M., Gustafson, A. E. & Padgett, D. Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J. Neurosci. 20, 9004–9016 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Shen, W., Hernandez-Lopez, S., Tkatch, T., Held, J. E. & Surmeier, D. J. Kv1.2-containing K+ channels regulate subthreshold excitability of striatal medium spiny neurons. J. Neurophysiol. 91, 1337–1349 (2004).

    CAS  Google Scholar 

  53. 53

    Chan, C. S., Shigemoto, R., Mercer, J. N. & Surmeier, D. J. HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons. J. Neurosci. 24, 9921–9932 (2004).

    CAS  PubMed  Google Scholar 

  54. 54

    Puopolo, M., Raviola, E. & Bean, B. P. Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. J. Neurosci. 27, 645–656 (2007).

    CAS  PubMed  Google Scholar 

  55. 55

    Nam, S. C. & Hockberger, P. E. Analysis of spontaneous electrical activity in cerebellar Purkinje cells acutely isolated from postnatal rats. J. Neurobiol. 33, 18–32 (1997).

    CAS  PubMed  Google Scholar 

  56. 56

    Callaway, J. C. & Ross, W. N. Spatial distribution of synaptically activated sodium concentration changes in cerebellar Purkinje neurons. J. Neurophysiol. 77, 145–152 (1997).

    CAS  PubMed  Google Scholar 

  57. 57

    Hausser, M. & Clark, B. A. Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19, 665–678 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Jenerick, H. Phase plane trajectories of the muscle spike potential. Biophys. J. 3, 363–377 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Hodgkin, A. L., Huxley, A. F. & Katz, B. Measurement of current-voltage relations in the membrane of the giant axon of Loligo. J. Physiol. 116, 424–448 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Colbert, C. M. & Johnston, D. Axonal action-potential initiation and Na+ channel densities in the soma and axon initial segment of subicular pyramidal neurons. J. Neurosci. 16, 6676–6686 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Clark, B. A., Monsivais, P., Branco, T., London, M. & Hausser, M. The site of action potential initiation in cerebellar Purkinje neurons. Nature Neurosci. 8, 137–139 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Martina, M. & Jonas, P. Functional differences in Na+ channel gating between fast-spiking interneurones and principal neurones of rat hippocampus. J. Physiol. 505, 593–603 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Maurice, N., Tkatch, T., Meisler, M., Sprunger, L. K. & Surmeier, D. J. D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons. J. Neurosci. 21, 2268–2277 (2001).

    CAS  PubMed  Google Scholar 

  64. 64

    Ptak, K. et al. Sodium currents in medullary neurons isolated from the pre-Botzinger complex region. J. Neurosci. 25, 5159–5170 (2005).

    CAS  PubMed  Google Scholar 

  65. 65

    Baranauskas, G. & Martina, M. Sodium currents activate without a Hodgkin-and-Huxley-type delay in central mammalian neurons. J. Neurosci. 26, 671–684 (2006).

    CAS  PubMed  Google Scholar 

  66. 66

    Armstrong, C. M. & Bezanilla, F. Inactivation of the sodium channel. II. Gating current experiments. J. Gen. Physiol. 70, 567–590 (1977).

    CAS  PubMed  Google Scholar 

  67. 67

    Bezanilla, F. & Armstrong, C. M. Inactivation of the sodium channel. I. Sodium current experiments. J. Gen. Physiol. 70, 549–566 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Engel, D. & Jonas, P. Presynaptic action potential amplification by voltage-gated Na+ channels in hippocampal mossy fiber boutons. Neuron 45, 405–417 (2005).

    CAS  PubMed  Google Scholar 

  69. 69

    Neumcke, B. & Stampfli, R. Sodium currents and sodium-current fluctuations in rat myelinated nerve fibres. J. Physiol. 329, 163–184 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Neumcke, B., Schwarz, J. R. & Stampfli, R. A comparison of sodium currents in rat and frog myelinated nerve: normal and modified sodium inactivation. J. Physiol. 382, 175–191 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Naundorf, B., Wolf, F. & Volgushev, M. Unique features of action potential initiation in cortical neurons. Nature 440, 1060–1063 (2006).

    CAS  PubMed  Google Scholar 

  72. 72

    McCormick, D. A., Shu, Y. & Yu, Y. Neurophysiology: Hodgkin and Huxley model — still standing? Nature 445, E1—E2 (2007).

    CAS  PubMed  Google Scholar 

  73. 73

    Raman, I. M. & Bean, B. P. Inactivation and recovery of sodium currents in cerebellar Purkinje neurons: evidence for two mechanisms. Biophys. J. 80, 729–737 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Grieco, T. M., Malhotra, J. D., Chen, C., Isom, L. L. & Raman, I. M. Open-channel block by the cytoplasmic tail of sodium channel β4 as a mechanism for resurgent sodium current. Neuron 45, 233–244 (2005). Presents evidence for a likely molecular mechanism underlying resurgent sodium currents.

    CAS  Google Scholar 

  75. 75

    Afshari, F. S. et al. Resurgent Na currents in four classes of neurons of the cerebellum. J. Neurophysiol. 92, 2831–2843 (2004).

    CAS  PubMed  Google Scholar 

  76. 76

    Magistretti, J., Castelli, L., Forti, L. & D'Angelo, E. Kinetic and functional analysis of transient, persistent and resurgent sodium currents in rat cerebellar granule cells in situ: an electrophysiological and modelling study. J. Physiol. 573, 83–106 (2006). State-of-the-art combination of voltage-clamp analysis of currents and modelling of firing, using a model with nine distinct conductances including an allosteric sodium channel model.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Enomoto, A., Han, J. M., Hsiao, C. F., Wu, N. & Chandler, S. H. Participation of sodium currents in burst generation and control of membrane excitability in mesencephalic trigeminal neurons. J. Neurosci. 26, 3412–3422 (2006).

    CAS  PubMed  Google Scholar 

  78. 78

    Leao, R. N., Naves, M. M., Leao, K. E. & Walmsley, B. Altered sodium currents in auditory neurons of congenitally deaf mice. Eur. J. Neurosci. 24, 1137–1146 (2006).

    PubMed  Google Scholar 

  79. 79

    Cummins, T. R., Dib-Hajj, S. D., Herzog, R. I. & Waxman, S. G. Nav1.6 channels generate resurgent sodium currents in spinal sensory neurons. FEBS Lett. 579, 2166–2170 (2005).

    CAS  PubMed  Google Scholar 

  80. 80

    Khaliq, Z. M., Gouwens, N. W. & Raman, I. M. The contribution of resurgent sodium current to high-frequency firing in Purkinje neurons: an experimental and modeling study. J. Neurosci. 23, 4899–4912 (2003).

    CAS  PubMed  Google Scholar 

  81. 81

    Sah, P. & McLachlan, E. M. Potassium currents contributing to action potential repolarization and the afterhyperpolarization in rat vagal motoneurons. J. Neurophysiol. 68, 1834–1841 (1992).

    CAS  PubMed  Google Scholar 

  82. 82

    Sah, P. Ca2+-activated K+ currents in neurones: types, physiological roles and modulation. Trends Neurosci. 19, 150–154 (1996).

    CAS  PubMed  Google Scholar 

  83. 83

    Shao, L. R., Halvorsrud, R., Borg-Graham, L. & Storm, J. F. The role of BK-type Ca2+-dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells. J. Physiol. 521, 135–146 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Sah, P. & Faber, E. S. Channels underlying neuronal calcium-activated potassium currents. Prog. Neurobiol. 66, 345–353 (2002).

    CAS  PubMed  Google Scholar 

  85. 85

    Faber, E. S. & Sah, P. Physiological role of calcium-activated potassium currents in the rat lateral amygdala. J. Neurosci. 22, 1618–1628 (2002).

    CAS  PubMed  Google Scholar 

  86. 86

    Faber, E. S. & Sah, P. Ca2+-activated K+ (BK) channel inactivation contributes to spike broadening during repetitive firing in the rat lateral amygdala. J. Physiol. 552, 483–497 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Sun, X., Gu, X. Q. & Haddad, G. G. Calcium influx via L- and N-type calcium channels activates a transient large-conductance Ca2+-activated K+ current in mouse neocortical pyramidal neurons. J. Neurosci. 23, 3639–3648 (2003).

    CAS  PubMed  Google Scholar 

  88. 88

    Goldberg, J. A. & Wilson, C. J. Control of spontaneous firing patterns by the selective coupling of calcium currents to calcium-activated potassium currents in striatal cholinergic interneurons. J. Neurosci. 25, 10230–10238 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Storm, J. F. Potassium currents in hippocampal pyramidal cells. Prog. Brain Res. 83, 161–187 (1990).

    CAS  PubMed  Google Scholar 

  90. 90

    Chen, W., Zhang, J. J., Hu, G. Y. & Wu, C. P. Different mechanisms underlying the repolarization of narrow and wide action potentials in pyramidal cells and interneurons of cat motor cortex. Neuroscience 73, 57–68 (1996).

    CAS  PubMed  Google Scholar 

  91. 91

    Lancaster, B. & Nicoll, R. A. Properties of two calcium-activated hyperpolarizations in rat hippocampal neurones. J. Physiol. 389, 187–203 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Storm, J. F. Intracellular injection of a Ca2+ chelator inhibits spike repolarization in hippocampal neurons. Brain Res. 435, 387–392 (1987).

    CAS  PubMed  Google Scholar 

  93. 93

    Marrion, N. V. & Tavalin, S. J. Selective activation of Ca2+-activated K+ channels by co-localized Ca2+ channels in hippocampal neurons. Nature 395, 900–905 (1998).

    CAS  PubMed  Google Scholar 

  94. 94

    Grunnet, M. & Kaufmann, W. A. Coassembly of big conductance Ca2+-activated K+ channels and L-type voltage-gated Ca2+ channels in rat brain. J. Biol. Chem. 279, 36445–36453 (2004).

    CAS  PubMed  Google Scholar 

  95. 95

    Berkefeld, H. et al. BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+ signaling. Science 314, 615–620 (2006).

    CAS  PubMed  Google Scholar 

  96. 96

    Muller, A., Kukley, M., Uebachs, M., Beck, H. & Dietrich, D. Nanodomains of single Ca2+ channels contribute to action potential repolarization in cortical neurons. J. Neurosci. 27, 483–495 (2007).

    PubMed  Google Scholar 

  97. 97

    Bennett, B. D., Callaway, J. C. & Wilson, C. J. Intrinsic membrane properties underlying spontaneous tonic firing in neostriatal cholinergic interneurons. J. Neurosci. 20, 8493–8503 (2000). A combination of current-clamp, voltage-clamp and calcium imaging to determine the ionic mechanism of pacemaking in tonically active cholinergic neurons of the striatum.

    CAS  PubMed  Google Scholar 

  98. 98

    Taddese, A. & Bean, B. P. Subthreshold sodium current from rapidly inactivating sodium channels drives spontaneous firing of tuberomammillary neurons. Neuron 33, 587–600 (2002).

    CAS  PubMed  Google Scholar 

  99. 99

    Viana, F., Bayliss, D. A. & Berger, A. J. Multiple potassium conductances and their role in action potential repolarization and repetitive firing behavior of neonatal rat hypoglossal motoneurons. J. Neurophysiol. 69, 2150–2163 (1993).

    CAS  PubMed  Google Scholar 

  100. 100

    Williams, S., Serafin, M., Muhlethaler, M. & Bernheim, L. Distinct contributions of high- and low-voltage-activated calcium currents to afterhyperpolarizations in cholinergic nucleus basalis neurons of the guinea pig. J. Neurosci. 17, 7307–7315 (1997).

    CAS  PubMed  Google Scholar 

  101. 101

    Pineda, J. C., Waters, R. S. & Foehring, R. C. Specificity in the interaction of HVA Ca2+ channel types with Ca2+-dependent AHPs and firing behavior in neocortical pyramidal neurons. J. Neurophysiol. 79, 2522–2534 (1998).

    CAS  PubMed  Google Scholar 

  102. 102

    Wolfart, J. & Roeper, J. Selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons. J. Neurosci. 22, 3404–3413 (2002).

    CAS  PubMed  Google Scholar 

  103. 103

    Hallworth, N. E., Wilson, C. J. & Bevan, M. D. Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro. J. Neurosci. 23, 7525–7542 (2003).

    CAS  PubMed  Google Scholar 

  104. 104

    Womack, M. D., Chevez, C. & Khodakhah, K. Calcium-activated potassium channels are selectively coupled to P/Q-type calcium channels in cerebellar Purkinje neurons. J. Neurosci. 24, 8818–8822 (2004).

    CAS  PubMed  Google Scholar 

  105. 105

    Nedergaard, S. A Ca2+-independent slow afterhyperpolarization in substantia nigra compacta neurons. Neuroscience 125, 841–852 (2004).

    CAS  PubMed  Google Scholar 

  106. 106

    Wolfart, J., Neuhoff, H., Franz, O. & Roeper, J. Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. J. Neurosci. 21, 3443–3456 (2001).

    CAS  PubMed  Google Scholar 

  107. 107

    Walter, J. T., Alvina, K., Womack, M. D., Chevez, C. & Khodakhah, K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nature Neurosci. 9, 389–397 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Raman, I. M. & Bean, B. P. Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J. Neurosci. 19, 1663–1674 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Jackson, A. C., Yao, G. L. & Bean, B. P. Mechanism of spontaneous firing in dorsomedial suprachiasmatic nucleus neurons. J. Neurosci. 24, 7985–7998 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Llinás, R., Sugimori, M. & Simon, S. M. Transmission by presynaptic spike-like depolarization in the squid giant synapse. Proc. Natl Acad. Sci. USA 79, 2415–2419 (1982).

    PubMed  PubMed Central  Google Scholar 

  111. 111

    Jackson, M. B., Konnerth, A. & Augustine, G. J. Action potential broadening and frequency-dependent facilitation of calcium signals in pituitary nerve terminals. Proc. Natl Acad. Sci. USA 88, 380–384 (1991).

    CAS  PubMed  Google Scholar 

  112. 112

    Borst, J. G. & Sakmann, B. Effect of changes in action potential shape on calcium currents and transmitter release in a calyx-type synapse of the rat auditory brainstem. Philos. Trans. R. Soc. Lond. B Biol. Sci. 354, 347–355 (1999). Action potential clamp experiments on presynaptic terminals (calyx of Held) showing that calcium channels are activated with high efficacy by action potentials.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Bischofberger, J., Geiger, J. R. & Jonas, P. Timing and efficacy of Ca2+ channel activation in hippocampal mossy fiber boutons. J. Neurosci. 22, 10593–10602 (2002).

    CAS  PubMed  Google Scholar 

  114. 114

    Yang, Y. M. & Wang, L. Y. Amplitude and kinetics of action potential-evoked Ca2+ current and its efficacy in triggering transmitter release at the developing calyx of held synapse. J. Neurosci. 26, 5698–5708 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Fernandez, F. R., Mehaffey, W. H., Molineux, M. L. & Turner, R. W. High-threshold K+ current increases gain by offsetting a frequency-dependent increase in low-threshold K+ current. J. Neurosci. 25, 363–371 (2005).

    CAS  PubMed  Google Scholar 

  116. 116

    Akemann, W. & Knopfel, T. Interaction of Kv3 potassium channels and resurgent sodium current influences the rate of spontaneous firing of Purkinje neurons. J. Neurosci. 26, 4602–4612 (2006).

    CAS  PubMed  Google Scholar 

  117. 117

    Storm, J. F. Action potential repolarization and a fast after-hyperpolarization in rat hippocampal pyramidal cells. J. Physiol. 385, 733–759 (1987). Analysis using pharmacology and ionic substitution of the potassium currents underlying spike repolarization, fast, medium and slow afterhyperpolarizations in CA1 pyramidal neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Locke, R. E. & Nerbonne, J. M. Three kinetically distinct Ca2+-independent depolarization-activated K+ currents in callosal-projecting rat visual cortical neurons. J. Neurophysiol. 78, 2309–2320 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Locke, R. E. & Nerbonne, J. M. Role of voltage-gated K+ currents in mediating the regular-spiking phenotype of callosal-projecting rat visual cortical neurons. J. Neurophysiol. 78, 2321–2335 (1997).

    CAS  PubMed  Google Scholar 

  120. 120

    Golding, N. L., Jung, H. Y., Mickus, T. & Spruston, N. Dendritic calcium spike initiation and repolarization are controlled by distinct potassium channel subtypes in CA1 pyramidal neurons. J. Neurosci. 19, 8789–8798 (1999).

    CAS  PubMed  Google Scholar 

  121. 121

    Kang, J., Huguenard, J. R. & Prince, D. A. Voltage-gated potassium channels activated during action potentials in layer V neocortical pyramidal neurons. J. Neurophysiol. 83, 70–80 (2000).

    CAS  PubMed  Google Scholar 

  122. 122

    Wu, R. L. & Barish, M. E. Two pharmacologically and kinetically distinct transient potassium currents in cultured embryonic mouse hippocampal neurons. J. Neurosci. 12, 2235–2246 (1992).

    CAS  PubMed  Google Scholar 

  123. 123

    Wu, R. L. & Barish, M. E. Modulation of a slowly inactivating potassium current, ID, by metabotropic glutamate receptor activation in cultured hippocampal pyramidal neurons. J. Neurosci. 19, 6825–6837 (1999).

    CAS  PubMed  Google Scholar 

  124. 124

    Riazanski, V. et al. Functional and molecular analysis of transient voltage-dependent K+ currents in rat hippocampal granule cells. J. Physiol. 537, 391–406 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Kim, J., Wei, D. S. & Hoffman, D. A. Kv4 potassium channel subunits control action potential repolarization and frequency-dependent broadening in rat hippocampal CA1 pyramidal neurones. J. Physiol. 569, 41–57 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Yuan, W., Burkhalter, A. & Nerbonne, J. M. Functional role of the fast transient outward K+ current IA in pyramidal neurons in (rat) primary visual cortex. J. Neurosci. 25, 9185–9194 (2005).

    CAS  PubMed  Google Scholar 

  127. 127

    Shibata, R. et al. A-type K+ current mediated by the Kv4 channel regulates the generation of action potential in developing cerebellar granule cells. J. Neurosci. 20, 4145–4155 (2000).

    CAS  PubMed  Google Scholar 

  128. 128

    Sheng, M., Tsaur, M. L., Jan, Y. N. & Jan, L. Y. Subcellular segregation of two A-type K+ channel proteins in rat central neurons. Neuron 9, 271–284 (1992).

    CAS  PubMed  Google Scholar 

  129. 129

    Storm, J. F. Temporal integration by a slowly inactivating K+ current in hippocampal neurons. Nature 336, 379–381 (1988). Description of I D as a subthreshold, slowly inactivating potassium current sensitive to low concentrations of 4-aminopyridine and distinct from I A and delayed-rectifier potassium currents.

    CAS  PubMed  Google Scholar 

  130. 130

    Stansfeld, C. E., Marsh, S. J., Halliwell, J. V. & Brown, D. A. 4-Aminopyridine and dendrotoxin induce repetitive firing in rat visceral sensory neurones by blocking a slowly inactivating outward current. Neurosci. Lett. 64, 299–304 (1986).

    CAS  PubMed  Google Scholar 

  131. 131

    Bekkers, J. M. & Delaney, A. J. Modulation of excitability by α-dendrotoxin-sensitive potassium channels in neocortical pyramidal neurons. J. Neurosci. 21, 6553–6560 (2001).

    CAS  PubMed  Google Scholar 

  132. 132

    Guan, D., Lee, J. C., Higgs, M. H., Spain, W. J. & Foehring, R. C. Functional roles of Kv1 channels in neocortical pyramidal neurons. J. Neurophysiol. 97, 1931–1940 (2007).

    CAS  PubMed  Google Scholar 

  133. 133

    Spain, W. J., Schwindt, P. C. & Crill, W. E. Two transient potassium currents in layer V pyramidal neurones from cat sensorimotor cortex. J. Physiol. 434, 591–607 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Ma, M. & Koester, J. Consequences and mechanisms of spike broadening of R20 cells in Aplysia californica. J. Neurosci. 15, 6720–6734 (1995).

    CAS  PubMed  Google Scholar 

  135. 135

    Ma, M. & Koester, J. The role of K+ currents in frequency-dependent spike broadening in Aplysia R20 neurons: a dynamic-clamp analysis. J. Neurosci. 16, 4089–4101 (1996). Combines the use of action potential clamp and dynamic clamp to analyse the changes in ionic currents underlying frequency-dependent spike broadening in an Aplysia neuron.

    CAS  PubMed  Google Scholar 

  136. 136

    Connor, J. A. & Stevens, C. F. Voltage clamp studies of a transient outward membrane current in gastropod neural somata. J. Physiol. 213, 21–30 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Connor, J. A. & Stevens, C. F. Prediction of repetitive firing behaviour from voltage clamp data on an isolated neurone soma. J. Physiol. 213, 31–53 (1971). Classic pair of papers describing I A in a snail neuron and using a computer model to analyse how it enables steady low-frequency firing.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Dodson, P. D., Barker, M. C. & Forsythe, I. D. Two heteromeric Kv1 potassium channels differentially regulate action potential firing. J. Neurosci. 22, 6953–6961 (2002).

    CAS  PubMed  Google Scholar 

  139. 139

    McKay, B. E., Molineux, M. L., Mehaffey, W. H. & Turner, R. W. Kv1 K+ channels control Purkinje cell output to facilitate postsynaptic rebound discharge in deep cerebellar neurons. J. Neurosci. 25, 1481–1492 (2005).

    CAS  PubMed  Google Scholar 

  140. 140

    Golomb, D., Yue, C. & Yaari, Y. Contribution of persistent Na+ current and M-type K+ current to somatic bursting in CA1 pyramidal cells: combined experimental and modeling study. J. Neurophysiol. 96, 1912–1926 (2006).

    CAS  PubMed  Google Scholar 

  141. 141

    Crill, W. E. Persistent sodium current in mammalian central neurons. Annu. Rev. Physiol. 58, 349–362 (1996).

    CAS  PubMed  Google Scholar 

  142. 142

    Brumberg, J. C., Nowak, L. G. & McCormick, D. A. Ionic mechanisms underlying repetitive high-frequency burst firing in supragranular cortical neurons. J. Neurosci. 20, 4829–4843 (2000).

    CAS  PubMed  Google Scholar 

  143. 143

    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. 545, 783–805 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Astman, N., Gutnick, M. J. & Fleidervish, I. A. Persistent sodium current in layer 5 neocortical neurons is primarily generated in the proximal axon. J. Neurosci. 26, 3465–3473 (2006).

    CAS  PubMed  Google Scholar 

  145. 145

    Vervaeke, K., Hu, H., Graham, L. J. & Storm, J. F. Contrasting effects of the persistent Na+ current on neuronal excitability and spike timing. Neuron 49, 257–270 (2006). Clear illustration of the context-sensitivity of the role of a given conductance, using dynamic clamp and an unusually detailed model of firing (incorporating 11 voltage-dependent conductances) to analyse counter-intuitive effects of a persistent sodium current on the firing patterns of CA1 pyramidal neurons.

    CAS  PubMed  Google Scholar 

  146. 146

    Maurice, N. et al. D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons. J. Neurosci. 24, 10289–10301 (2004). Combines current clamp, voltage clamp, and modelling to show that modest changes in sodium channel gating produced by dopamine can produce surprisingly large effects on the frequency of spontaneous firing.

    CAS  PubMed  Google Scholar 

  147. 147

    Magistretti, J. & Alonso, A. Biophysical properties and slow voltage-dependent inactivation of a sustained sodium current in entorhinal cortex layer-II principal neurons: a whole-cell and single-channel study. J. Gen. Physiol. 114, 491–509 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Magistretti, J. & Alonso, A. Fine gating properties of channels responsible for persistent sodium current generation in entorhinal cortex neurons. J. Gen. Physiol. 120, 855–873 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Azouz, R., Jensen, M. S. & Yaari, Y. Ionic basis of spike after-depolarization and burst generation in adult rat hippocampal CA1 pyramidal cells. J. Physiol. 492, 211–223 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Gutfreund, Y., yarom, Y. & Segev, I. Subthreshold oscillations and resonant frequency in guinea-pig cortical neurons: physiology and modelling. J. Physiol. 483, 621–640 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Hutcheon, B., Miura, R. M. & Puil, E. Subthreshold membrane resonance in neocortical neurons. J. Neurophysiol. 76, 683–697 (1996).

    CAS  PubMed  Google Scholar 

  152. 152

    White, J. A., Klink, R., Alonso, A. & Kay, A. R. Noise from voltage-gated ion channels may influence neuronal dynamics in the entorhinal cortex. J. Neurophysiol. 80, 262–269 (1998).

    CAS  PubMed  Google Scholar 

  153. 153

    Wu, N. et al. Persistent sodium currents in mesencephalic v neurons participate in burst generation and control of membrane excitability. J. Neurophysiol. 93, 2710–2722 (2005).

    CAS  PubMed  Google Scholar 

  154. 154

    Llinás, R. & Yarom, Y. Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances. J. Physiol. 315, 549–567 (1981).

    PubMed  PubMed Central  Google Scholar 

  155. 155

    Jahnsen, H. & Llinás, R. Ionic basis for the electro-responsiveness and oscillatory properties of guinea-pig thalamic neurones in vitro. J. Physiol. 349, 227–247 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Williams, S. R., Toth, T. I., Turner, J. P., Hughes, S. W. & Crunelli, V. The 'window' component of the low threshold Ca2+ current produces input signal amplification and bistability in cat and rat thalamocortical neurones. J. Physiol. 505, 689–705 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Henze, D. A. & Buzsaki, G. Action potential threshold of hippocampal pyramidal cells in vivo is increased by recent spiking activity. Neuroscience 105, 121–130 (2001).

    CAS  PubMed  Google Scholar 

  158. 158

    de Polavieja, G. G., Harsch, A., Kleppe, I., Robinson, H. P. & Juusola, M. Stimulus history reliably shapes action potential waveforms of cortical neurons. J. Neurosci. 25, 5657–5665 (2005).

    CAS  PubMed  Google Scholar 

  159. 159

    Korngreen, A., Kaiser, K. M. & Zilberter, Y. Subthreshold inactivation of voltage-gated K+ channels modulates action potentials in neocortical bitufted interneurones from rats. J. Physiol. 562, 421–437 (2005).

    CAS  PubMed  Google Scholar 

  160. 160

    Alle, H. & Geiger, J. R. Combined analog and action potential coding in hippocampal mossy fibers. Science 311, 1290–1293 (2006).

    CAS  Google Scholar 

  161. 161

    Shu, Y., Hasenstaub, A., Duque, A., Yu, Y. & McCormick, D. A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential. Nature 441, 761–765 (2006). References 160 and 161 demonstrate, in two types of glutamatergic neurons, that the electrotonic length constant of the axon is long enough (400–450 μm) that changes in membrane potential at the soma can influence membrane potential at presynaptic terminals.

    CAS  Google Scholar 

  162. 162

    Goldstein, S. A., Bockenhauer, D., O'Kelly, I. & Zilberberg, N. Potassium leak channels and the KCNK family of two-P-domain subunits. Nature Rev. Neurosci. 2, 175–184 (2001).

    CAS  Google Scholar 

  163. 163

    Meuth, S. G. et al. Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. J. Neurophysiol. 96, 1517–1529 (2006).

    CAS  PubMed  Google Scholar 

  164. 164

    Mathie, A. Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J. Physiol. 578, 377–385 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Berg, A. P. & Bayliss, D. A. Striatal cholinergic interneurons express a receptor-insensitive homomeric TASK-3-like background K+ current. J. Neurophysiol. 97, 1546–1552 (2007).

    CAS  PubMed  Google Scholar 

  166. 166

    Eggermann, E. et al. The wake-promoting hypocretin-orexin neurons are in an intrinsic state of membrane depolarization. J. Neurosci. 23, 1557–1562 (2003).

    CAS  PubMed  Google Scholar 

  167. 167

    Pape, H. C. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol. 58, 299–327 (1996).

    CAS  PubMed  Google Scholar 

  168. 168

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

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    McCormick, D. A. & Pape, H. C. Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J. Physiol. 431, 291–318 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Maccaferri, G. & McBain, C. J. The hyperpolarization-activated current (Ih) and its contribution to pacemaker activity in rat CA1 hippocampal stratum oriens-alveus interneurones. J. Physiol. 497, 119–130 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Wilson, C. J. & Callaway, J. C. Coupled oscillator model of the dopaminergic neuron of the substantia nigra. J. Neurophysiol. 83, 3084–3100 (2000).

    CAS  PubMed  Google Scholar 

  172. 172

    Stocker, M. Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nature Rev. Neurosci. 5, 758–770 (2004).

    CAS  Google Scholar 

  173. 173

    Pedarzani, P. et al. Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current IAHP and modulates the firing properties of hippocampal pyramidal neurons. J. Biol. Chem. 280, 41404–41411 (2005).

    CAS  PubMed  Google Scholar 

  174. 174

    Gu, N., Vervaeke, K., Hu, H. & Storm, J. F. Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells. J. Physiol. 566, 689–715 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Lawrence, J. J. et al. Somatodendritic Kv7/KCNQ/M channels control interspike interval in hippocampal interneurons. J. Neurosci. 26, 12325–12338 (2006).

    CAS  PubMed  Google Scholar 

  176. 176

    Womack, M. D. & Khodakhah, K. Characterization of large conductance Ca2+-activated K+ channels in cerebellar Purkinje neurons. Eur. J. Neurosci. 16, 1214–1222 (2002).

    PubMed  Google Scholar 

  177. 177

    Edgerton, J. R. & Reinhart, P. H. Distinct contributions of small and large conductance Ca2+-activated K+ channels to rat Purkinje neuron function. J. Physiol. 548, 53–69 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Vogalis, F., Storm, J. F. & Lancaster, B. SK channels and the varieties of slow after-hyperpolarizations in neurons. Eur. J. Neurosci. 18, 3155–3166 (2003).

    PubMed  Google Scholar 

  179. 179

    Bond, C. T. et al. Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J. Neurosci. 24, 5301–5306 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Villalobos, C., Shakkottai, V. G., Chandy, K. G., Michelhaugh, S. K. & Andrade, R. SKCa channels mediate the medium but not the slow calcium-activated afterhyperpolarization in cortical neurons. J. Neurosci. 24, 3537–3542 (2004).

    CAS  PubMed  Google Scholar 

  181. 181

    Shah, M. M., Javadzadeh-Tabatabaie, M., Benton, D. C., Ganellin, C. R. & Haylett, D. G. Enhancement of hippocampal pyramidal cell excitability by the novel selective slow-afterhyperpolarization channel blocker 3-(triphenylmethylaminomethyl)pyridine (UCL2077). Mol. Pharmacol. 70, 1494–1502 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Wong, R. K. & Prince, D. A. Afterpotential generation in hippocampal pyramidal cells. J. Neurophysiol. 45, 86–97 (1981).

    CAS  PubMed  Google Scholar 

  183. 183

    White, G., Lovinger, D. M. & Weight, F. F. Transient low-threshold Ca2+ current triggers burst firing through an afterdepolarizing potential in an adult mammalian neuron. Proc. Natl Acad. Sci. USA 86, 6802–6806 (1989).

    CAS  PubMed  Google Scholar 

  184. 184

    Jensen, M. S., Azouz, R. & Yaari, Y. Spike after-depolarization and burst generation in adult rat hippocampal CA1 pyramidal cells. J. Physiol. 492, 199–210 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    Swensen, A. M. & Bean, B. P. Ionic mechanisms of burst firing in dissociated Purkinje neurons. J. Neurosci. 23, 9650–9663 (2003).

    CAS  PubMed  Google Scholar 

  186. 186

    Metz, A. E., Jarsky, T., Martina, M. & Spruston, N. R-type calcium channels contribute to afterdepolarization and bursting in hippocampal CA1 pyramidal neurons. J. Neurosci. 25, 5763–5773 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Haj-Dahmane, S. & Andrade, R. Calcium-activated cation nonselective current contributes to the fast afterdepolarization in rat prefrontal cortex neurons. J. Neurophysiol. 78, 1983–1989 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Wong, R. K. & Stewart, M. Different firing patterns generated in dendrites and somata of CA1 pyramidal neurones in guinea-pig hippocampus. J. Physiol. 457, 675–687 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Andreasen, M. & Lambert, J. D. Regenerative properties of pyramidal cell dendrites in area CA1 of the rat hippocampus. J. Physiol. 483, 421–441 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Magee, J. C. & Carruth, M. Dendritic voltage-gated ion channels regulate the action potential firing mode of hippocampal CA1 pyramidal neurons. J. Neurophysiol. 82, 1895–1901 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191

    Williams, S. R. & Stuart, G. J. Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons. J. Physiol. 521, 467–482 (1999). Incisive analysis of the mechanism of all-or-none bursting in layer 5 pyramidal neurons, showing the crucial role of activation of dendritic sodium channels and calcium channels.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    D'Angelo, E. et al. Theta-frequency bursting and resonance in cerebellar granule cells: experimental evidence and modeling of a slow k+-dependent mechanism. J. Neurosci. 21, 759–770 (2001).

    CAS  PubMed  Google Scholar 

  193. 193

    Achard, P. & De Schutter, E. Complex parameter landscape for a complex neuron model. PLoS Comput. Biol. 2, e94 (2006).

    PubMed  PubMed Central  Google Scholar 

  194. 194

    Goldman, M. S., Golowasch, J., Marder, E. & Abbott, L. F. Global structure, robustness, and modulation of neuronal models. J. Neurosci. 21, 5229–5238 (2001). Remarkable demonstration — using modelling together with dynamic clamp experiments — that nearly identical bursting behaviour can be produced by highly variable combinations of levels of five conductances, even when small changes in a given conductance can modulate firing.

    CAS  PubMed  Google Scholar 

  195. 195

    Golowasch, J., Goldman, M. S., Abbott, L. F. & Marder, E. Failure of averaging in the construction of a conductance-based neuron model. J. Neurophysiol. 87, 1129–1131 (2002).

    PubMed  Google Scholar 

  196. 196

    Marder, E. & Goaillard, J. M. Variability, compensation and homeostasis in neuron and network function. Nature Rev. Neurosci. 7, 563–574 (2006).

    CAS  Google Scholar 

  197. 197

    Swensen, A. M. & Bean, B. P. Robustness of burst firing in dissociated purkinje neurons with acute or long-term reductions in sodium conductance. J. Neurosci. 25, 3509–3520 (2005).

    CAS  PubMed  Google Scholar 

  198. 198

    Sharp, A. A., O'Neil, M. B., Abbott, L. F. & Marder, E. Dynamic clamp: computer-generated conductances in real neurons. J. Neurophysiol. 69, 992–995 (1993).

    CAS  PubMed  Google Scholar 

  199. 199

    Robinson, H. P. & Kawai, N. Injection of digitally synthesized synaptic conductance transients to measure the integrative properties of neurons. J. Neurosci. Methods 49, 157–165 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Prinz, A. A., Abbott, L. F. & Marder, E. The dynamic clamp comes of age. Trends Neurosci. 27, 218–224 (2004).

    CAS  PubMed  Google Scholar 

  201. 201

    Goldman, L. & Schauf, C. L. Inactivation of the sodium current in Myxicola giant axons. Evidence for coupling to the activation process. J. Gen. Physiol. 59, 659–675 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    Aldrich, R. W., Corey, D. P. & Stevens, C. F. A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature 306, 436–441 (1983).

    CAS  PubMed  Google Scholar 

  203. 203

    Vandenberg, C. A. & Bezanilla, F. A sodium channel gating model based on single channel, macroscopic ionic, and gating currents in the squid giant axon. Biophys. J. 60, 1511–1533 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Kuo, C. C. & Bean, B. P. Na+ channels must deactivate to recover from inactivation. Neuron 12, 819–829 (1994).

    CAS  PubMed  Google Scholar 

  205. 205

    Serrano, J. R., Perez-Reyes, E. & Jones, S. W. State-dependent inactivation of the alpha1G T-type calcium channel. J. Gen. Physiol. 114, 185–201 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206

    Beck, E. J., Bowlby, M., An, W. F., Rhodes, K. J. & Covarrubias, M. Remodelling inactivation gating of Kv4 channels by KChIP1, a small-molecular-weight calcium-binding protein. J. Physiol. 538, 691–706 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I am grateful to M. Puopolo, M. Martina, B. Carter and A. Swensen for permission to use their unpublished data, and to them, Z. Khaliq and A. Jackson for much helpful discussion. Supported by the National Institute of Neurological Diseases and Stroke (NS36855).

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Glossary

Heterologous expression

Expression of protein molecules by the injection of complementary RNA into the cytoplasm (or complementary DNA into the nucleus) of host cells that do not normally express the proteins, such as Xenopus oocytes or mammalian cell lines.

Spike

Another term for an action potential (especially the portion with the most rapidly changing voltage).

Projection neurons

Neurons with relatively long axons that project out of a local circuit (distinct from interneurons).

Bursting

The firing of a rapid series of several action potentials with very short (less than 5 ms) interspike intervals.

Adaptation

Slowing or cessation of firing during a maintained stimulus.

Initial segment

The slender initial region of an axon where it originates from an axon hillock of the cell body (or sometimes from a major dendrite), characterized by the fasciculation of microtubules.

Node of Ranvier

Interruption of the myelin sheath in a myelinated nerve fibre.

Outside-out patch

A variant of the patch-clamp technique in which a patch of plasma membrane covers the tip of the electrode, with the outside of the membrane exposed to the bathing solution.

Activation

Conformational change of a channel molecule from a closed (non-conducting) to an open (conducting) state (for voltage-dependent channels, this is usually by depolarization of the membrane).

Subthreshold voltages

Voltages negative to the threshold voltage (Box 1) for action potential firing (which is typically in the range of −55 mV to −40 mV in mammalian central neurons).

Tetrodotoxin

(TTX). Alkaloid toxin derived from Fugu puffer fish that is a potent and highly selective blocker of voltage-dependent sodium channels.

Inactivation

Conformational change of a channel molecule to a closed state that differs from the closed 'resting' state in that the channel cannot be opened (for example, by further depolarization).

4-aminopyridine

Potassium channel blocker that inhibits some potassium channels (including Kv3 family channels and a subset of Kv1 family subunits) with a high relative potency and others (such as Kv4 channels) more weakly, or not all.

Tetraethylammonium ion

(TEA). When applied externally, this blocks some types of voltage-activated potassium channels (notably BK and Kv3 family channels) and not others.

Delayed-rectifier current

Depolarization-activated potassium current similar to that of the squid axon, with relatively slow activation and minimal (or very slow) inactivation.

e-fold

Measure of steepness of voltage-dependent activation, associated with a description by the Boltzmann function; e-fold increase is a 2.72-fold increase.

Midpoint

Voltage at which activation is half-maximal.

Rebound bursting

Firing of a burst of action potentials when a hyperpolarizing influence (such as inhibitory postsynaptic potential) is terminated.

Electrotonic length constant

Measure of the distance over which a voltage change imposed at one point in a cable-like structure decays to 1/e (37%).

Pacemaking neurons

Neurons that fire spontaneous action potentials in a regular, rhythmic manner.

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Bean, B. The action potential in mammalian central neurons. Nat Rev Neurosci 8, 451–465 (2007). https://doi.org/10.1038/nrn2148

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