Action Potentials Are Critical for the Propagation of Focally Elicited Spreading Depolarizations

Abstract

Spreading depolarizations (SDs) of gray matter occur in the brain in different pathologic conditions, and cause varying degrees of tissue damage depending on the extent of metabolic burden on the tissue. As might be expected for such large depolarizations, neurons exhibit bursts of action potentials (APs) as the wave propagates. However, the specific role of APs in SD propagation is unclear. This is potentially consequential, since sodium channel modulation has not been considered as a therapeutic target for SD-associated disorders, because of ambiguous experimental evidence. Using whole-cell electrophysiology and single-photon imaging in acute cortical slices from male C57Bl6 mice, we tested the effects of AP blockade on SDs generated by two widely used induction paradigms. We found that AP blockade using tetrodotoxin (TTX) restricted propagation of focally induced SDs, and significantly reduced the amplitude of neuronal depolarization, as well as its Ca²⁺ load. TTX also abolished the suppression of spontaneous synaptic activity that is a hallmark of focally induced SD. In contrast, TTX did not affect the propagation of SD induced by global superfusion of high [K⁺]_e containing artificial CSF (ACSF). Thus, we show that voltage-gated sodium channel (Na_v)-mediated neuronal AP bursts are critical for the propagation and downstream effects of focally induced SD but are less important when the ionic balance of the extracellular space is already compromised. In doing so we corroborate the notion that two different SD induction paradigms, each relevant to different clinical situations, vary significantly in their characteristics and potentially their response to treatment.

SIGNIFICANCE STATEMENT Our findings suggest that voltage-gated sodium channel (Na_v) channels have a critical role in the propagation and downstream neural effects of focally induced spreading depolarization (SD). As SDs are likely induced focally in many disease conditions, these studies support sodium channel modulation, a previously underappreciated therapeutic option in SD-associated disorders, as a viable approach.