Subverting the hegemony of the synapse: Complicity of neurons, astrocytes, and vasculature in spreading depression and pathology of the cerebral cortex

Contrary to Golgi's “reticular” theory of nervous structure, it is clear that the synapse rules over communication among nerve cells. Spreading depression, however, does not follow synaptic pathways. It sweeps across gray matter like a political revolution, ignoring structural boundaries and carefully established regulatory mechanisms. Neurons form alliances with their usually subordinate partners, the astrocytes, to cause a perturbation of function that strains resources necessary for recovery. Innocent bystanders, the blood vessels, are obliged to try to ameliorate the disturbance but may not be able to respond optimally in the chaotic environment. Under extreme circumstances, a purge of some of the instigators may ensue. This anarchic picture of interactions among the elements of nervous tissue does little to rescue the reticular theory that was one of Golgi's most important intellectual offerings. Nevertheless, it reminds us that the behavior of populations of nerve cells need not necessarily be limited by the pathways dictated by synaptic junctions. Spreading depression is a multifactorial phenomenon, in which intense depolarization of neurons and/or astrocytes leads to perturbations that include release of K⁺, release of glutamate, increase in intracellular Ca⁺⁺, release of ATP and local anoxia, as well as vascular changes. This process plays a role in migraine and contributes to the damage produced by brain anoxia, trauma, stroke, and subarachnoid hemorrhage. It may provide clues to new treatments for the damaged brain.