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 1

Filament middle cerebral artery occlusion in TgNotch3R90C and TgNotch3R169C cohorts.

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Filament middle cerebral artery occlusion in TgNotch3R90C and TgNotch3R1...
(A) Left: A representative image of 2,3,5-triphenyltetrazolium chloride–stained (TTC-stained) coronal sections 24 hours after transient filament middle cerebral artery occlusion (fMCAO). Infarct can be seen as nonstained tissue involving MCA territory. Right: Representative laser Doppler flowmetry (LDF) tracing shows decrease in regional cerebral blood flow (CBF) after common carotid artery occlusion (CCAO) followed by MCAO and reperfusion. Shaded segments indicate where CBF was measured relative to baseline. (B) Infarct volume (indirect method), neurological deficit score, and CBF after CCAO, during MCAO, and after reperfusion in the entire TgNotch3R90C cohort (all ages pooled). In addition to nontransgenic WT mice, transgenic mice overexpressing the human WT Notch 3 (TgNotch3WT mice) were used to control for overexpression in TgNotch3R90C mice. One-way ANOVA followed by Tukey’s multiple comparisons for infarct volume and neurological deficit score (*P = 0.0035 vs. WT, *P = 0.0074 vs. TgNotch3WT; †P = 0.0039 vs. WT, †P = 0.0372 vs. TgNotch3WT) and 2-way ANOVA for repeated measures followed by Šidák’s multiple comparisons for CBF. ANOVA P values are also shown on each panel. Sample sizes are provided in Table 4. (C) Infarct volume (indirect method), neurological deficit score, and CBF after CCAO, during MCAO, and after reperfusion in the entire TgNotch3R169C cohort (all ages pooled, Table 4). Unpaired t test for infarct volume and neurological deficit score, and two-way ANOVA for repeated measures followed by Šidák’s multiple comparisons for CBF (*P = 0.0326, TgNotch3R169C vs. WT). ANOVA P values are also shown on each panel. Mean ± SD. Sample sizes are provided in Table 4.