Rapid Neuronal Ultrastructure Disruption and Recovery during Spreading Depolarization-Induced Cytotoxic Edema

Cereb Cortex. 2020 Sep 3;30(10):5517-5531. doi: 10.1093/cercor/bhaa134.


Two major pathogenic events that cause acute brain damage during neurologic emergencies of stroke, head trauma, and cardiac arrest are spreading depolarizing waves and the associated brain edema that course across the cortex injuring brain cells. Virtually nothing is known about how spreading depolarization (SD)-induced cytotoxic edema evolves at the ultrastructural level immediately after insult and during recovery. In vivo 2-photon imaging followed by quantitative serial section electron microscopy was used to assess synaptic circuit integrity in the neocortex of urethane-anesthetized male and female mice during and after SD evoked by transient bilateral common carotid artery occlusion. SD triggered a rapid fragmentation of dendritic mitochondria. A large increase in the density of synapses on swollen dendritic shafts implies that some dendritic spines were overwhelmed by swelling or merely retracted. The overall synaptic density was unchanged. The postsynaptic dendritic membranes remained attached to axonal boutons, providing a structural basis for the recovery of synaptic circuits. Upon immediate reperfusion, cytotoxic edema mainly subsides as affirmed by a recovery of dendritic ultrastructure. Dendritic recuperation from swelling and reversibility of mitochondrial fragmentation suggests that neurointensive care to improve tissue perfusion should be paralleled by treatments targeting mitochondrial recovery and minimizing the occurrence of SDs.

Keywords: cytotoxic edema; dendritic beading; dendritic spines; mitochondria; stroke; synapse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / physiopathology*
  • Brain / ultrastructure*
  • Brain Edema / etiology
  • Brain Edema / pathology*
  • Brain Edema / physiopathology*
  • Cortical Spreading Depression*
  • Dendrites / ultrastructure
  • Female
  • Male
  • Mice, Transgenic
  • Microscopy, Electron
  • Neurons / physiology*
  • Neurons / ultrastructure*
  • Optical Imaging
  • Stroke / complications*
  • Synapses / ultrastructure