Abstract
The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na+ channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na+ channel density. We found that low-threshold Nav1.6 and high-threshold Nav1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na+ current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Nav1.6 promotes action potential initiation, whereas proximal Nav1.2 promotes its backpropagation to the soma.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Clark, B.A., Monsivais, P., Branco, T., London, M. & Hausser, M. The site of action potential initiation in cerebellar Purkinje neurons. Nat. Neurosci. 8, 137–139 (2005).
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).
Colbert, C.M. & Pan, E. Ion channel properties underlying axonal action potential initiation in pyramidal neurons. Nat. Neurosci. 5, 533–538 (2002).
Mainen, Z.F., Joerges, J., Huguenard, J.R. & Sejnowski, T.J. A model of spike initiation in neocortical pyramidal neurons. Neuron 15, 1427–1439 (1995).
Milojkovic, B.A., Wuskell, J.P., Loew, L.M. & Antic, S.D. Initiation of sodium spikelets in basal dendrites of neocortical pyramidal neurons. J. Membr. Biol. 208, 155–169 (2005).
Stuart, G., Schiller, J. & Sakmann, B. Action potential initiation and propagation in rat neocortical pyramidal neurons. J. Physiol. (Lond.) 505, 617–632 (1997).
Stuart, G., Spruston, N., Sakmann, B. & Hausser, M. Action potential initiation and backpropagation in neurons of the mammalian CNS. Trends Neurosci. 20, 125–131 (1997).
Coombs, J.S., Curtis, D.R. & Eccles, J.C. The interpretation of spike potentials of motoneurones. J. Physiol. (Lond.) 139, 198–231 (1957).
Eccles, J.C. The Physiology of Nerve Cells (The Johns Hopkins Press, Baltimore, 1957).
Fatt, P. Sequence of events in synaptic activation of a motoneurone. J. Neurophysiol. 20, 61–80 (1957).
Fuortes, M.G., Frank, K. & Becker, M.C. Steps in the production of motoneuron spikes. J. Gen. Physiol. 40, 735–752 (1957).
Meeks, J.P. & Mennerick, S. Action potential initiation and propagation in CA3 pyramidal axons. J. Neurophysiol. 97, 3460–3472 (2007).
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).
Kole, M.H. & Stuart, G.J. Is action potential threshold lowest in the axon? Nat. Neurosci. 11, 1253–1255 (2008).
Dodge, F.A. & Cooley, J.W. Action potential of the motoneuron. IBM J. Res. Develop. 17, 219–229 (1973).
Moore, J.W., Stockbridge, N. & Westerfield, M. On the site of impulse initiation in a neurone. J. Physiol. (Lond.) 336, 301–311 (1983).
Rapp, M., Yarom, Y. & Segev, I. Modeling back propagating action potential in weakly excitable dendrites of neocortical pyramidal cells. Proc. Natl. Acad. Sci. USA 93, 11985–11990 (1996).
Van Wart, A., Trimmer, J.S. & Matthews, G. Polarized distribution of ion channels within microdomains of the axon initial segment. J. Comp. Neurol. 500, 339–352 (2007).
Inda, M.C., DeFelipe, J. & Munoz, A. Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. Proc. Natl. Acad. Sci. USA 103, 2920–2925 (2006).
Kole, M.H., Letzkus, J.J. & Stuart, G.J. Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron 55, 633–647 (2007).
Shu, Y., Yu, Y., Yang, J. & McCormick, D.A. Selective control of cortical axonal spikes by a slowly inactivating K+ current. Proc. Natl. Acad. Sci. USA 104, 11453–11458 (2007).
Howard, A., Tamas, G. & Soltesz, I. Lighting the chandelier: new vistas for axo-axonic cells. Trends Neurosci. 28, 310–316 (2005).
Kole, M.H. et al. Action potential generation requires a high sodium channel density in the axon initial segment. Nat. Neurosci. 11, 178–186 (2008).
Lorincz, A. & Nusser, Z. Cell type–dependent molecular composition of the axon initial segment. J. Neurosci. 28, 14329–14340 (2008).
Boiko, T. et al. Functional specialization of the axon initial segment by isoform-specific sodium channel targeting. J. Neurosci. 23, 2306–2313 (2003).
Royeck, M. et al. Role of axonal Nav1.6 sodium channels in action potential initiation of CA1 pyramidal neurons. J. Neurophysiol. 100, 2361–2380 (2008).
Duflocq, A., Le Bras, B., Bullier, E., Couraud, F. & Davenne, M. Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments. Mol. Cell. Neurosci. 39, 180–192 (2008).
Rush, A.M., Dib-Hajj, S.D. & Waxman, S.G. Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones. J. Physiol. (Lond.) 564, 803–815 (2005).
Boiko, T. et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30, 91–104 (2001).
Kaplan, M.R. et al. Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Neuron 30, 105–119 (2001).
Komai, S. et al. Postsynaptic excitability is necessary for strengthening of cortical sensory responses during experience-dependent development. Nat. Neurosci. 9, 1125–1133 (2006).
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).
Palmer, L.M. & Stuart, G.J. Site of action potential initiation in layer 5 pyramidal neurons. J. Neurosci. 26, 1854–1863 (2006).
Wollner, D.A. & Catterall, W.A. Localization of sodium channels in axon hillocks and initial segments of retinal ganglion cells. Proc. Natl. Acad. Sci. USA 83, 8424–8428 (1986).
Naundorf, B., Wolf, F. & Volgushev, M. Unique features of action potential initiation in cortical neurons. Nature 440, 1060–1063 (2006).
Shu, Y., Hasenstaub, A. & McCormick, D.A. Turning on and off recurrent balanced cortical activity. Nature 423, 288–293 (2003).
Steriade, M., Nunez, A. & Amzica, F. A novel slow (<1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J. Neurosci. 13, 3252–3265 (1993).
Yu, Y., Shu, Y. & McCormick, D.A. Cortical action potential backpropagation explains spike threshold variability and rapid-onset kinetics. J. Neurosci. 28, 7260–7272 (2008).
McCormick, D.A., Shu, Y. & Yu, Y. Neurophysiology: Hodgkin and Huxley model—still standing? Nature 445, E1–2; discussion E2–3 (2007).
Colbert, C.M. & Johnston, D. Protein kinase C activation decreases activity-dependent attenuation of dendritic Na+ current in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 79, 491–495 (1998).
Bi, G.Q. & Poo, M.M. Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength and postsynaptic cell type. J. Neurosci. 18, 10464–10472 (1998).
Kampa, B.M., Clements, J., Jonas, P. & Stuart, G.J. Kinetics of Mg2+ unblock of NMDA receptors: implications for spike timing–dependent synaptic plasticity. J. Physiol. (Lond.) 556, 337–345 (2004).
Kampa, B.M., Letzkus, J.J. & Stuart, G.J. Requirement of dendritic calcium spikes for induction of spike timing–dependent synaptic plasticity. J. Physiol. (Lond.) 574, 283–290 (2006).
Markram, H., Lubke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997).
Sjöström, P.J., Turrigiano, G.G. & Nelson, S.B. Rate, timing, and cooperativity jointly determine cortical synaptic plasticity. Neuron 32, 1149–1164 (2001).
Sather, W., Dieudonne, S., MacDonald, J.F. & Ascher, P. Activation and desensitization of N-methyl-D-aspartate receptors in nucleated outside-out patches from mouse neurones. J. Physiol. (Lond.) 450, 643–672 (1992).
Hodgkin, A.L. & Huxley, A.F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. (Lond.) 117, 500–544 (1952).
Hines, M.L. & Carnevale, N.T. The NEURON simulation environment. Neural Comput. 9, 1179–1209 (1997).
Mainen, Z.F. & Sejnowski, T.J. Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 382, 363–366 (1996).
Engel, D. & Jonas, P. Presynaptic action potential amplification by voltage-gated Na+ channels in hippocampal mossy fiber boutons. Neuron 45, 405–417 (2005).
Acknowledgements
We thank M.M. Poo, D.A. McCormick and M.H. Kole for their valuable comments on this work. We are also grateful to Y. Yu for his help in computer modeling. This work was supported by the 973 Program (2006CB806600), a Shanghai Commission of Science and Technology grant (06DJ14010), the Shanghai Pujiang Program (07PJ14108), the Hundreds of Talents Program and Knowledge Innovation Project from Chinese Academy of Sciences (KSCX2-YW-R-102), and Projects of the Scientific Research Foundation of the State Human Resource Ministry and the Education Ministry.
Author information
Authors and Affiliations
Contributions
W.H. performed the patch-clamp and whole-cell recording experiments, simulations, and data analysis. C.T. carried out the immunostaining experiments. T.L. performed the sharp electrode recordings. M.Y. and H.H. helped with data analysis and simulations. Y.S. designed the experiments and wrote the paper.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 (PDF 1486 kb)
Rights and permissions
About this article
Cite this article
Hu, W., Tian, C., Li, T. et al. Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation. Nat Neurosci 12, 996–1002 (2009). https://doi.org/10.1038/nn.2359
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2359
This article is cited by
-
Therapeutic efficacy of voltage-gated sodium channel inhibitors in epilepsy
Acta Epileptologica (2023)
-
Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin
Nature Communications (2023)
-
Heterogeneity of voltage gated sodium current density between neurons decorrelates spiking and suppresses network synchronization in Scn1b null mouse models
Scientific Reports (2023)
-
Bi-directional Control of Synaptic Input Summation and Spike Generation by GABAergic Inputs at the Axon Initial Segment
Neuroscience Bulletin (2023)
-
Projection-Specific Heterogeneity of the Axon Initial Segment of Pyramidal Neurons in the Prelimbic Cortex
Neuroscience Bulletin (2023)