Mechanistic insight into the initiation of spreading depolarizations: Is it really all about potassium?

Abstract

Cortical tissue, when subjected to certain electrical, mechanical, thermal or chemical disturbances, can undergo a widescale disruption of neuronal ionic electrochemical gradients, termed spreading depolarization (SD). SDs propagate slowly across the brain (∼2–9 mm min⁻¹), coinciding with the depression of spontaneous and evoked electrophysiological activity; hence, the near synonymous term spreading depression (Somjen, 2004). It was this suppression of activity, discerned in rabbit models of experimental epilepsy, that first alerted Aristides Leão to the phenomenon in (Leao, 1944).

Since then, various technological developments have provided new ways to identify and characterize SDs. Intracellular recordings show the near complete breakdown in ionic concentration gradients during SD, causing a sustained shift in neuronal intracellular potential to near 0 mV (Somjen, 2004). The disturbance propagates outward from the point of stress in a regenerative, all-or-nothing wave, independent of the stimulus. The neuronal depolarization is accompanied by glial depolarization as extracellular potassium, [K⁺]_o, increases and, importantly, normally reverses after a few seconds to minutes. Transient alterations in blood flow and metabolic rate, cellular swelling, and the release of most neurotransmitters and neuromodulators within the depolarized tissue occur concomitantly. The cellular swelling causes subtle changes in reflectance and light scattering, allowing SDs to be easily visualized using intrinsic optical imaging (Somjen, 2004). Clinically, the recent introduction of wide-band recording facilities is helping record SDs in humans, whereas previously, most EEG machines used high-pass filtering to prevent drift in the recordings from overloading the amplifier, excluding SD events identified from DC shifts and low frequency components of the local field potential. The recognition that SDs are a prominent feature in many human pathologies has greatly increased interest in understanding these events.

SDs have now been implicated in multiple different clinical neurological conditions, including migraine with aura, traumatic brain injury, intracranial and subarachnoid haemorrhage, ischaemic stroke, seizure and sudden unexpected death in epilepsy (SUDEP). Identifying the distinct molecular and electrophysiological mechanisms underlying SD initiation is essential to understanding their role in neuronal health and disease and, more importantly, what therapeutic approaches may be taken to reduce brain injury resulting from these various neuropathologies. In this review, we discuss how our understanding of SD initiation has been shaped by the choice of experimental models, and how new models of SD induction invite us to reexamine the underlying mechanism.