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

• Published in: The Journal of clinical investigation Vol. 132; no. 8; pp. 1 - 12
• Main Authors: Oka, Fumiaki, Lee, Jeong Hyun, Yuzawa, Izumi, Li, Mei, von Bornstaedt, Daniel, Eikermann-Haerter, Katharina, Qin, Tao, Chung, David Y, Sadeghian, Homa, Seidel, Jessica L, Imai, Takahiko, Vuralli, Doga, Platt, Rosangela M, Nelson, Mark T, Joutel, Anne, Sakadzic, Sava, Ayata, Cenk
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15-04-2022
• Subjects: Age; Animal models; Animals; Biomedical research; Blood flow; Brain; CADASIL; CADASIL - genetics; Cerebral blood flow; Cerebral infarction; Cerebral ischemia; Complications and side effects; Dementia; Dementia disorders; Development and progression; Gene mutations; Genetic aspects; Genotype & phenotype; Genotypes; Headache; Health aspects; Hemodynamics; Homeostasis; Human health and pathology; Infarction, Middle Cerebral Artery; Ischemia; Lasers; Leukoaraiosis; Leukoencephalopathy; Life Sciences; Medical research; Medicine, Experimental; Mice; Migraine; Mutants; Mutation; Neurological diseases; Neurons and Cognition; Neuroscience; Perfusion; Potassium; Potassium imbalance; Receptors, Notch - genetics; Risk factors; Rodents; Smooth muscle; Spreading; Spreading depression; Stroke; Transgenic animals; Transgenic mice; Veins & arteries; United States; Microcirculation; Neuroscience; Stroke; Potassium channels; small vessel disease; transgenic mice; viability threshold; cerebral ischemia; spreading depolarization
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI149759

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.