CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis
Fumiaki Oka, … , Sava Sakadzic, Cenk Ayata
Fumiaki Oka, … , Sava Sakadzic, Cenk Ayata
Published February 24, 2022
Citation Information: J Clin Invest. 2022;132(8):e149759. https://doi.org/10.1172/JCI149759.
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Research Article Neuroscience

CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis

Abstract

Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular K+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL.

Authors

Fumiaki Oka, Jeong Hyun Lee, Izumi Yuzawa, Mei Li, Daniel von Bornstaedt, Katharina Eikermann-Haerter, Tao Qin, David Y. Chung, Homa Sadeghian, Jessica L. Seidel, Takahiko Imai, Doga Vuralli, Rosangela M. Platt, Mark T. Nelson, Anne Joutel, Sava Sakadzic, Cenk Ayata

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Figure 6

Proposed gliovascular mechanism of extracellular K+ regulation when local buffering mechanisms are exceeded during spreading depolarizations.

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Proposed gliovascular mechanism of extracellular K+ regulation when loca...
(i) Upon intense depolarization states, such as anoxic or spreading depolarization, extracellular K+ concentration ([K+]e) can rise above the 10–12 mM ceiling. (b) Astrocytes play a major role in regulating [K+]e via rapid uptake and spatial buffering through the astrocytic syncytium. (c) Astrocytes send their end feet, almost completely encasing the cerebral vasculature, including the capillary bed, providing a route for gliovascular K+ siphoning. (d) The massive rise in [K+]e during an SD might also facilitate direct entry of K+ into the perivascular space to reach the capillary endothelium. (e) Astrocyte end feet have high K+ conductance, in part, due to BK channels activated by intracellular Ca2+ elevations, such as those observed during SD, and release large amounts of K+ into the tight perivascular space. (f) This perivascular K+ is then taken up by the endothelial Na+/K+-ATPase, which is densely — and asymmetrically — localized on the abluminal membranes. (g) Endothelial cells then release the K+ into the blood stream via channels and/or pumps on the luminal membrane, including Kir2.1, which is known to be activated by elevated perivascular [K+]e. (h) Notch3R169C mutation is associated with impaired endothelial Kir2.1 channel function, linking CADASIL to impaired vascular K+ clearance.