BRIEF RESEARCH REPORT article
Front. Cell. Neurosci.
Sec. Cellular Neurophysiology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1668329
Pharmacological inhibition of all known major inward cationic currents does not block the induction of spreading depolarizations
Provisionally accepted
Preston C Withers1,2Allen Jones1Kojo Bawuah Afran-Okese1,2Bailey Calder1Hunter J Morrill1T Luke Shafer1,2Dallin S Nevers1,2Jacob H Norby1,2Rebeca Acosta1,2Benjamin T Bikman1
Arminda Suli1
R Ryley Parrish1,2*- 1Brigham Young University, Provo, United States
- 2Brigham Young University Neuroscience Center, Provo, United States
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Spreading depolarization (SD) is a wave of profound cellular depolarization that propagates primarily across gray matter of central nervous system tissue and causes a near-complete collapse of ionic gradients. Implicated in neuropathologies including seizures, migraine with aura, traumatic brain injury, and stroke, SD is experimentally induced in animals by electrical stimulation, mechanical injury, hypoxia, elevated extracellular potassium, and various other techniques. Despite extensive research, the mechanisms underlying SD initiation remain unclear. Prior research in rodents found that simultaneously blocking sodium, calcium, and glutamatergic (AMPA and NMDA) channels prevents SD induction whereas inhibiting any two of these three currents is insufficient. This suggests that SD induction could be a product of overstimulation of any single known inward cationic current. However, some researchers propose that SD induction occurs via an unknown "SD channel." To further explore the role of known inward cationic currents in SD induction, we applied high potassium to two biological models, namely zebrafish and mice. First, we developed a novel ex vivo zebrafish model to assess SD induction in the optic tectum. Using KCl microinjection and DC recordings, we found that inhibition of sodium, calcium, and glutamatergic channels significantly decreased SD amplitude but never blocked SD induction in the zebrafish optic tectum. Similar pharmacological experiments in hippocampal mouse slices (CA1 subregion) also confirmed that SDs persist despite the same pharmacological cocktail. These findings suggest that additional mechanisms beyond sodium, calcium, and glutamatergic signaling contribute to SD induction, supporting the hypothesis that an unknown channel is critical in SD physiology.
Keywords: Spreading depression, Pharmacology, Electrophysiology, Zebrafish, optic tectum, mouse slices, Ex vivo models
Received: 17 Jul 2025; Accepted: 24 Sep 2025.
Copyright: © 2025 Withers, Jones, Afran-Okese, Calder, Morrill, Shafer, Nevers, Norby, Acosta, Bikman, Suli and Parrish. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: R Ryley Parrish, ryley_parrish@byu.edu
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