Cellular and network mechanisms of spreading depolarization

Spreading depolarization (SD) denotes a slowly propagating wave of ionic redistribution resulting in neuronal and glial depolarization, cellular swelling, vascular alterations, and metabolic challenge. Tissue characteristics, including brain region and energy availability, influence both entry into and recovery from SD. Though many paradigms reliably induce SD, a nuanced debate surrounds the fundamental mechanism underlying SD initiation and the primary conductances involved. Emerging mechanistic hypotheses of SD induction share a common theme of disruption in ionic homeostasis, often involving sodium–potassium ATPase insufficiency. The prevalence of SD in traumatic brain injury, stroke, migraine with aura, and seizures underscores the clinical relevance of understanding the physiological basis of SD. This Staying Current article describes the potential mechanisms underlying SD initiation, propagation, recovery, and clinical impact from a mechanistic standpoint.