Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation

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.

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Figure 1: Polarized distribution of Na+ channel subtypes.
Figure 2: Estimates of Na+ channel density at the soma and the axon with regular and giant outside-out patch recording.
Figure 3: Comparison of voltage dependence of somatic and axonal Na+ currents.
Figure 4: The low activation threshold of axonal Na+ channels is not attributed to cooperative activation.
Figure 5: Simulations indicate distinct functions of AIS Nav1.6 and Nav1.2 in action potential initiation and backpropagation to the soma.
Figure 6: Vm dependence of action potential backpropagation.
Figure 7: The threshold of somatic action potential is dependent on the preceding Vm.
Figure 8: Voltage threshold of somatodendritic potential is independent of the preceding Vm.

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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.

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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

Correspondence to Yousheng Shu.

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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

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