Microglia interact with dendritic spines and regulate spine numbers after brain injury following resuscitation from a cardiac arrest

Abstract

Cognitive dysfunction is common after global cerebral ischemic injury caused by a cardiac arrest and is likely due in part to changes in synaptic function. Increasing evidence suggests microglial cells regulate synapse architecture and activity in various pathophysiologic conditions. However, the role of microglia in mediating synaptic injury after global cerebral ischemia has not been addressed. In this study, we use a mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR) to evaluate changes that occur in the numbers and morphology of both dendritic spines and microglia in the hippocampus after global cerebral ischemia. We also directly evaluate the interaction between dendritic spines and microglia after CA/CPR and assess how altering microglial numbers after the injury affects spine numbers. Our findings highlight that CA/CPR results in hippocampal spine loss that occurs in parallel with an increase in microglia numbers. Morphologic analysis of microglial cells demonstrates that CA/CPR leads to acute changes in cellular structure consistent with reactivity to the ischemic injury. We also show that microglia-spine contacts increase in the period following a CA/CPR injury along with co-localization between spines and phagocytic vesicles within microglia, suggesting a potential role for microglial engulfment in mediating spine loss. Finally, we demonstrate that pharmacologic depletion of microglia with PLX5622 after CA/CPR restores spine numbers in the injured brain. Collectively, these results emphasize the important role microglia exhibit in regulating synapse numbers in the setting of a CA/CPR injury and suggest targeting microglia-synapse interactions may improve cognitive outcomes following global ischemic brain injury.