Synchronous microglial calcium activity in the progression of ischemic stroke pathology
Petr Tvrdik1*, Ilyas Eli2, Punam Sawant-Pokam2, Khadijeh Sharifi1, Brenden Ronna2, Elizabeth W. J. Carlson2, Andrew Zayachkivsky2, K.C. Brennan2, F. Edward Dudek2, M. Yashar S. Kalani1 1University of Virginia, 2University of Utah *Corresponding author
Ischemic stroke is the third cause of death and the leading cause of disability in the United States. Microglia have been implicated in ischemic stroke pathobiology, but their specific functions remain poorly defined. Here we use the model of permanent middle cerebral artery occlusion (MCAo) to study microglial responses to ischemic pathophysiology. Using intravital imaging of genetically encoded indicators of calcium signaling, we have demonstrated that microglia display spreading waves of calcium activity. These waves first appear approximately 3 hours after occlusion and reoccur, on average, once per hour. Extracellular electrophysiological measurements show that microglial calcium activity correlates with DC voltage deflections. Therefore, these waves are associated with cortical spreading depolarizations triggered by ischemic stroke. Our findings demonstrate a novel mechanism whereby microglia are active participants in the pathobiology of ischemic stroke, which may provide new avenues for therapeutic interventions.