Astroglial and neuronal integrity during cortical spreading depolarization

In the minutes, hours and even days following stroke or traumatic brain injury (TBI), cerebral gray matter undergoes recurring waves of depolarization that spread across neurons and astrocytes. Originating near the site of injury, these waves of spreading depolarization migrate through regions of compromised blood flow, consuming precious energy and expanding the initial site of infarct or TBI. The collapseof ion gradients is the hallmark of spreading depolarization. This causes rapid astroglial and neuronal swelling (i.e. cytotoxic edema) and dendritic beading with spine loss which represents acute damage to synaptic circuitry. Spreading depolarization has long been associated with migraine aura and it was recently recognized as a novel mechanism of injury in stroke and TBI patients. Despite testing of numerous neuroprotective agents in clinical trials no neuroprotective drugs have proven helpful. This can be partially attributed to the inadequate understanding of the dynamic cellular processes that promote brain damage during recurring waves of spreading depolarization. A surprisingly large therapeutic window exists to diminish the depolarizing and hemodynamic activity of spreading depolarization waves and thus reduce subsequent secondary brain injury. In this chapter, the impact of spreading depolarization waves on neuronal and astroglial cellular integrity is described.