Ransdell, J. L. | Search bioRxiv

bioRxiv2023

A reinterpretation of the relationship between persistent and resurgent sodium currents

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or non-inactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages, and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the Nav conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates. Significance StatementAcross neuronal cell types, the resurgent sodium current (INaR) is often implicated in driving high rates of repetitive firing. Using dynamic clamp, we determined INaR is ineffective at driving subsequent action potentials, and that the subthreshold persistent sodium current (INaP) is the critical parameter for scaling repetitive firing rates. We propose INaR measured in native neurons may reflect a mechanism by which the magnitude of INaP is fine-tuned.

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bioRxiv2021

Intrinsic Mechanisms in the Gating of Resurgent Na+ Currents

The resurgent component of the voltage-gated sodium current (INaR) is a depolarizing conductance, revealed on membrane hyperpolarizations following brief depolarizing voltage steps, which has been shown to contribute to regulating the firing properties of numerous neuronal cell types throughout the central and peripheral nervous systems. Although mediated by the same voltage-gated sodium (Nav) channels that underlie the transient and persistent Nav current components, the gating mechanisms that contribute to the generation of INaR remain unclear. Here, we characterized Nav currents in mouse cerebellar Purkinje neurons, and used tailored voltage-clamp protocols to define how the voltage and the duration of the initial membrane depolarization affect the amplitudes and kinetics of INaR. Using the acquired voltage-clamp data, we developed a novel Markov kinetic state model with parallel (fast and slow) inactivation pathways and, we show that this model reproduces the properties of the resurgent, as well as the transient and persistent, Nav currents recorded in (mouse) cerebellar Purkinje neurons. Based on the acquired experimental data and the simulations, we propose that resurgent Na+ influx occurs as a result of fast inactivating Nav channels transitioning into an open/conducting state on membrane hyperpolarization, and that the decay of INaR reflects the slow accumulation of recovered/opened Nav channels into a second, alternative and more slowly populated, inactivated state. Additional simulations reveal that extrinsic factors that affect the kinetics of fast or slow Nav channel inactivation and/or impact the relative distribution of Nav channels in the fast- and slow-inactivated states, such as the accessory Nav{beta}4 channel subunit, can modulate the amplitude of INaR. SUMMARYThe resurgent component of the voltage-gated sodium current (INaR) is revealed on membrane hyperpolarizations following brief depolarizing voltage steps that activate the rapidly activating and inactivating, transient Nav current (INaT). To probe the mechanisms contributing to the generation and properties of INaR, we combined whole-cell voltage-clamp recordings from mouse cerebellar Purkinje neurons with computational modeling to develop a novel, blocking particle-independent, model for the gating of INaR that involves two parallel inactivation pathways, and we show that this model recapitulates the detailed biophysical properties of INaR measured in mouse cerebellar Purkinje neurons.

neuroscience↗