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

Abstract

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.

Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci

“…2) together predicted SiD occurrence, and were suggestive of tissue edema irreversible after SD1. After establishing a link between osmotic stress and SiD occurrence, we set out to explore the reciprocal interaction between tissue swelling and SD/SiD, because SD has been proposed as the principal mechanism of neuronal cytotoxic edema Kirov et al, 2020).…”

Oxygen-Induced and pH-Induced Direct Current Artifacts on Invasive Platinum/Iridium Electrodes for Electrocorticography

“…The term SD describes the electrophysiological aspect, and the term cytotoxic edema describes the pathomorphological aspect of this process. Accordingly, SD is observed as a large negative direct current (DC) shift, two-photon microscopy shows neuronal swelling with a beaded morphology of neuronal dendrites during SD [2], and magnetic resonance imaging shows a propagating wave of diffusion restriction [3][4][5]. SDs occur during a plethora of clinical conditions, including migraine aura [6,7], ischemic stroke [8,9], traumatic brain injury [10,11], aneurysmal subarachnoid hemorrhage (aSAH) and delayed ischemic stroke [12][13][14], spontaneous intracerebral hemorrhage [15], subdural hematoma [16], development of brain death [17,18], and dying from circulatory arrest [19].…”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…A critical factor contributing to decreased CBF following stroke and implicating astrocytes are injury depolarizations, also known as Cortical Spreading Depressions or CSDs ( Takano et al, 2007 ; Attwell et al, 2010 ). CSDs are slowly propagating waves of neuronal and glial depolarization ( Lauritzen et al, 2011 ; Ayata and Lauritzen, 2015 ) that spontaneously occur within minutes after ischemic stroke and originate from the peri-infarct region ( Dreier, 2011 ; Lauritzen et al, 2011 ; Kao et al, 2014 ; Lauritzen and Strong, 2016 ; Kirov et al, 2020 ). CSDs impair recovery in rodent stroke models ( Risher et al, 2010 ; von Bornstadt et al, 2015 ) and correlate with clinical deterioration in stroke patients ( Nakamura et al, 2010 ; Lauritzen and Strong, 2016 ).…”