Spreading depolarizations are a key event in the pathophysiology of stroke, 
resulting in rapid dendritic beading, which represents acute damage to synaptic 
circuitry. The impact of spreading depolarizations on the real-time injury of 
astrocytes during ischemia is less clear. We used simultaneous in vivo 2-photon 
imaging and electrophysiological recordings in adult mouse somatosensory cortex 
to examine spreading depolarization-induced astroglial structural changes 
concurrently with signs of neuronal injury in the early periods of focal and 
global ischemia. Astrocytes in the metabolically compromised ischemic 
penumbra-like area showed a long lasting swelling response to spontaneous 
spreading depolarizations despite rapid dendritic recovery in a photothrombotic 
occlusion model of focal stroke. Astroglial swelling was often facilitated by 
recurrent depolarizations and the magnitude of swelling strongly correlated with 
the total duration of depolarization. In contrast, spreading 
depolarization-induced astroglial swelling was transient in normoxic healthy 
tissue. In a model of transient global ischemia, the occurrence of a single 
spreading depolarization elicited by a bilateral common carotid artery occlusion 
coincided with astroglial swelling alongside dendritic beading. With immediate 
reperfusion, dendritic beading subsides. Astroglial swelling was either 
transient during short ischemic periods distinguished by a short-lasting 
spreading depolarization, or persistent during severe ischemia characterized by 
a long-lasting depolarization with the ultraslow negative voltage component. We 
propose that persistent astroglial swelling is initiated and exacerbated during 
spreading depolarization in brain tissue with moderate to severe energy 
deficits, disrupting astroglial maintenance of normal homeostatic function thus 
contributing to the negative outcome of ischemic stroke as astrocytes fail to 
provide neuronal support.