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 2

Distal middle cerebral artery occlusion in TgNotch3R90C and TgNotch3R169C cohorts.

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Distal middle cerebral artery occlusion in TgNotch3R90C and TgNotch3R169...
(A) Resting CBF calculated using laser speckle contrast inverse correlation time values before distal middle cerebral artery occlusion (dMCAO) did not differ between CADASIL mutant mice and controls. Sample sizes are provided in Table 4. Student’s t test. (B) A representative laser speckle contrast image taken 60 minutes after dMCAO shows regions with severe (residual CBF <20%), moderate (21%–30%), and mild (31%–40%) CBF deficit. Composite bar graphs show the areas of severe, moderate, and mild CBF deficit in TgNotch3R90C and TgNotch3R169C mice and their respective controls (TgNotch3WT and WT) 60 minutes after dMCAO (all ages pooled). Two-way ANOVA for repeated measures. P values on each panel are those of main ANOVA. CBF deficit area is shown as mean ± SEM. (C) A representative laser speckle contrast image showing the perfusion defect during dMCAO (left) and 2,3,5-triphenyltetrazolium chloride–stained (TTC-stained) brain showing the infarct in the same brain 48 hours later (right). Images were spatially coregistered using surface landmarks. A line profile was drawn between lambda and the clip occluding the middle cerebral artery (yellow arrowhead). For each animal, CBF was plotted along the line profile as a function of distance from lambda using laser speckle images (bottom). The CBF at the infarct edge was determined (blue dotted lines), representing the CBF threshold for viability, below which tissue infarcted in each mouse. The average viability threshold was significantly higher in TgNotch3R90C vs. TgNotch3WT mice (all ages pooled). Unpaired t test.