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UBC Theses and Dissertations

Cellular mechanisms underlying cortical spreading depression Zhou, Ning


Cortical spreading depression (SD) is a slowly propagating wave of brain cell depolarization that manifests in several neurological conditions, including migraine with aura, ischemia and brain trauma. The unique pattern of SD propagation suggests that it arises from an unusual form of intercellular communication. To advance our understanding of SD, we used two-photon imaging, intrinsic optical imaging, electrophysiological recording, and amperometric glutamate biosensor measurement to study the mechanisms underlying SD propagation in acute isolated brain slices. In Chapter 2 we examined and compared the neuronal versus astrocytic changes in cellular processes which are fundamental to both cell types including cell volume, pH and metabolism during SD propagation. We found that SD was correlated in neurons with robust yet transient increased volume, intracellular acidification and mitochondrial depolarization. Our data indicated that a propagating large conductance during SD generated neuronal depolarization, which led to both calcium influx triggering metabolic changes and H⁺ entry. Notably, astrocytes did not exhibit changes in cell volume, pH or mitochondrial membrane potentials associated with SD but they did show alterations induced by changing external [K⁺]. This suggests that astrocytes are not the primary contributor to SD propagation but are instead activated passively by extracellular potassium accumulation. In Chapter 3 we used enzyme based glutamate electrodes to show that NMDA receptors likely at presynaptic sites, trigger SD by evoking glutamate release via vesicular exocytosis, independent of action potentials and voltage gated calcium channels. Both SD- and NMDA-induced vesicular exocytosis of glutamate are triggered by efflux of calcium from mitochondria via the mitochondrial Na⁺/Ca²⁺ exchanger. Through this mechanism NMDAR stimulation evokes a vicious cycle of glutamate-induced glutamate release. Diffusion of glutamate to more distant NMDARs will generate a slowly propagating regenerative glutamate release to cause widespread neuronal depolarization. These data offer support for the hypothesis that neuronal signaling pathways play a crucial role in propagation of SD and the following pathophysiological responses. Particularly, a novel form of NMDAR-dependent regenerative glutamate release is responsible for the cellular mechanisms that promote SD progression. In addition, this research may provide insight into possible clinical targets for treatment of SD-related neurological disorders.

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