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Role of Axonal Na_V1.6 Sodium Channels in Action Potential Initiation of CA1 Pyramidal Neurons

¹Department of Epileptology, University of Bonn Medical Center, Bonn, Germany; ²Helmholtz-Institute for Radiation and Nuclear Physics and ³Interdisciplinary Center for Complex Systems, University of Bonn, Bonn, Germany; and ⁴Department of Physiology, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel

Submitted 5 March 2008; accepted in final form 10 July 2008

In many neuron types, the axon initial segment (AIS) has the lowest threshold for action potential generation. Its active properties are determined by the targeted expression of specific voltage-gated channel subunits. We show that the Na⁺ channel Na_V1.6 displays a striking aggregation at the AIS of cortical neurons. To assess the functional role of this subunit, we used Scn8a^med mice that are deficient for Na_V1.6 subunits but still display prominent Na⁺ channel aggregation at the AIS. In CA1 pyramidal cells from Scn8a^med mice, we found a depolarizing shift in the voltage dependence of activation of the transient Na⁺ current (I_NaT), indicating that Na_V1.6 subunits activate at more negative voltages than other Na_V subunits. Additionally, persistent and resurgent Na⁺ currents were significantly reduced. Current-clamp recordings revealed a significant elevation of spike threshold in Scn8a^med mice as well as a shortening of the estimated delay between spike initiation at the AIS and its arrival at the soma. In combination with simulations using a realistic computer model of a CA1 pyramidal cell, our results imply that a hyperpolarized voltage dependence of activation of AIS Na_V1.6 channels is important both in determining spike threshold and localizing spike initiation to the AIS. In addition to altered spike initiation, Scn8a^med mice also showed a strongly reduced spike gain as expected with combined changes in persistent and resurgent currents and spike threshold. These results suggest that Na_V1.6 subunits at the AIS contribute significantly to its role as spike trigger zone and shape repetitive discharge properties of CA1 neurons.

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