A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents

Overview

Journal bioRxiv

Date 2024 Jan 8

PMID 38187680

Authors

Samuel P Brown

Ryan J Lawson

Jonathan D Moreno

Joseph L Ransdell

Affiliations

Soon will be listed here.

Abstract

The resurgent sodium current (I) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, I is thought to drive high rates of repetitive neuronal firing. However, I is often studied in combination with the persistent or non-inactivating portion of sodium currents (I). We used dynamic clamp to test how I and I individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned I does not scale repetitive firing rates due to its rapid decay at subthreshold voltages, and that subthreshold I is critical in regulating neuronal firing rate. Adjustments to the Nav conductance model used in these studies revealed I and I 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 I and Purkinje neuron repetitive firing rates.

References

Obata K, Ito M, Ochi R, Sato N . Pharmacological properties of the postsynaptic inhibition by Purkinje cell axons and the action of gamma-aminobutyric acid on deiters NEURONES. Exp Brain Res. 1967; 4(1):43-57. DOI: 10.1007/BF00235216. View

Raman I, Bean B . Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J Neurosci. 1999; 19(5):1663-74. PMC: 6782167. View

Hargus N, Nigam A, Bertram 3rd E, Patel M . Evidence for a role of Nav1.6 in facilitating increases in neuronal hyperexcitability during epileptogenesis. J Neurophysiol. 2013; 110(5):1144-57. PMC: 3763090. DOI: 10.1152/jn.00383.2013. View

Ransdell J, Moreno J, Bhagavan D, Silva J, Nerbonne J . Intrinsic mechanisms in the gating of resurgent Na currents. Elife. 2022; 11. PMC: 8824471. DOI: 10.7554/eLife.70173. View

Stuart G, Hausser M . Initiation and spread of sodium action potentials in cerebellar Purkinje cells. Neuron. 1994; 13(3):703-12. DOI: 10.1016/0896-6273(94)90037-x. View

Khaliq Z, Raman I . Relative contributions of axonal and somatic Na channels to action potential initiation in cerebellar Purkinje neurons. J Neurosci. 2006; 26(7):1935-44. PMC: 6674931. DOI: 10.1523/JNEUROSCI.4664-05.2006. View

Carter B, Giessel A, Sabatini B, Bean B . Transient sodium current at subthreshold voltages: activation by EPSP waveforms. Neuron. 2012; 75(6):1081-93. PMC: 3460524. DOI: 10.1016/j.neuron.2012.08.033. View

Raman I, Sprunger L, Meisler M, Bean B . Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice. Neuron. 1997; 19(4):881-91. DOI: 10.1016/s0896-6273(00)80969-1. View

Thach W . Discharge of Purkinje and cerebellar nuclear neurons during rapidly alternating arm movements in the monkey. J Neurophysiol. 1968; 31(5):785-97. DOI: 10.1152/jn.1968.31.5.785. View

10.

Chen Y, Yu F, Surmeier D, Scheuer T, Catterall W . Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C. Neuron. 2006; 49(3):409-20. DOI: 10.1016/j.neuron.2006.01.009. View

11.

Raman I, Bean B . Inactivation and recovery of sodium currents in cerebellar Purkinje neurons: evidence for two mechanisms. Biophys J. 2001; 80(2):729-37. PMC: 1301271. DOI: 10.1016/S0006-3495(01)76052-3. View

12.

Khaliq Z, Gouwens N, Raman I . The contribution of resurgent sodium current to high-frequency firing in Purkinje neurons: an experimental and modeling study. J Neurosci. 2003; 23(12):4899-912. PMC: 6741194. View

13.

Aman T, Raman I . Subunit dependence of Na channel slow inactivation and open channel block in cerebellar neurons. Biophys J. 2006; 92(6):1938-51. PMC: 1861793. DOI: 10.1529/biophysj.106.093500. View

14.

Silva J . Slow inactivation of Na(+) channels. Handb Exp Pharmacol. 2014; 221:33-49. DOI: 10.1007/978-3-642-41588-3_3. View

15.

Moreno J, Lewis T, Clancy C . Parameterization for In-Silico Modeling of Ion Channel Interactions with Drugs. PLoS One. 2016; 11(3):e0150761. PMC: 4786197. DOI: 10.1371/journal.pone.0150761. View

16.

Dib-Hajj S, Yang Y, Black J, Waxman S . The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci. 2012; 14(1):49-62. DOI: 10.1038/nrn3404. View

17.

Han C, Estacion M, Huang J, Vasylyev D, Zhao P, Dib-Hajj S . Human Na(v)1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J Neurophysiol. 2015; 113(9):3172-85. PMC: 4432682. DOI: 10.1152/jn.00113.2015. View

18.

Zemel B, Nevue A, Dagostin A, Lovell P, Mello C, von Gersdorff H . Resurgent Na currents promote ultrafast spiking in projection neurons that drive fine motor control. Nat Commun. 2021; 12(1):6762. PMC: 8604930. DOI: 10.1038/s41467-021-26521-3. View

19.

Womack M, Khodakhah K . Active contribution of dendrites to the tonic and trimodal patterns of activity in cerebellar Purkinje neurons. J Neurosci. 2002; 22(24):10603-12. PMC: 6758439. View

20.

Raman I . The Hodgkin-Huxley-Katz Prize Lecture: A Markov model with permeation-dependent gating that accounts for resurgent current of voltage-gated Na channels. J Physiol. 2023; 601(23):5147-5164. PMC: 10913027. DOI: 10.1113/JP285166. View