Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra.
Spontaneous spreading depolarizations (SDs) occur in the penumbra surrounding ischemic core. These SDs, often referred to as peri-infarct depolarizations, cause vasoconstriction and recruitment of the penumbra into the ischemic core in the critical first hours after focal ischemic stroke; however, the real-time spatiotemporal dynamics of SD-induced injury to synaptic circuitry in the penumbra remain unknown. A modified cortical photothrombosis model was used to produce a square-shaped lesion surrounding a penumbra-like "area at risk" in middle cerebral artery territory of mouse somatosensory cortex. Lesioning resulted in recurrent spontaneous SDs. In vivo two-photon microscopy of green fluorescent protein-expressing neurons in this penumbra-like area at risk revealed that SDs were temporally correlated with rapid (<6 s) dendritic beading. Dendrites quickly (<3 min) recovered between SDs to near-control morphology until the occurrence of SD-induced terminal dendritic injury, signifying acute synaptic damage. SDs are characterized by a breakdown of ion homeostasis that can be recovered by ion pumps if the energy supply is adequate. Indeed, the likelihood of rapid dendritic recovery between SDs was correlated with the presence of nearby flowing blood vessels, but the presence of such vessels was not always sufficient for rapid dendritic recovery, suggesting that energy needs for recovery exceeded energy supply of compromised blood flow. We propose that metabolic stress resulting from recurring SDs facilitates acute injury at the level of dendrites and dendritic spines in metabolically compromised tissue, expediting penumbral recruitment into the ischemic core.
Risher
W Christopher
WC
Graduate Program in Neuroscience, Medical College of Georgia, Augusta, Georgia 30912, USA.
Ard
Deborah
D
Yuan
Jianghe
J
Kirov
Sergei A
SA
D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D013181:Cortical Spreading Depression; D003712:Dendrites / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049229:Dendritic Spines / Q000000981:diagnostic imaging; D004569:Electroencephalography; D007089:Image Enhancement; D051379:Mice; D008822:Mice, Transgenic; D012008:Recurrence; D013003:Somatosensory Cortex / Q000000981:diagnostic imaging; D014463:Ultrasonography