Properties of an intermediate-duration inactivation process of the voltage-gated sodium conductance in rat hippocampal CA1 neurons

Rapid transmembrane flow of sodium ions produces the depolarizing phase of action potentials (APs) in most excitable tissue through voltage-gated sodium channels (Na_V). Macroscopic currents display rapid activation followed by fast inactivation (I_F) within milliseconds. Slow inactivation (I_S) has been subsequently observed in several preparations including neuronal tissues. I_S serves important physiological functions, but the kinetic properties are incompletely characterized, especially the operative timescales. Here we present evidence for an "intermediate inactivation" (I_I) process in rat hippocampal CA1 neurons with time constants of the order of 100 ms. The half-inactivation potentials (V_0.5) of steady-state inactivation curves were hyperpolarized by increasing conditioning pulse duration from 50 to 500 ms and could be described by a sum of Boltzmann relations. I_I state transitions were observed after opening as well as subthreshold potentials. Entry into I_I after opening was relatively insensitive to membrane potential, and recovery of I_I became more rapid at hyperpolarized potentials. Removal of fast inactivation with cytoplasmic papaine revealed time constants of I_Na decay corresponding to I_I and I_S with long depolarizations. Dynamic clamp revealed attenuation of trains of APs over the 10²-ms timescale, suggesting a functional role of I_I in repetitive firing accommodation. These experimental findings could be reproduced with a five-state Markov model. It is likely that I_I affects important aspects of hippocampal neuron response and may provide a drug target for sodium channel modulation.

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