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

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is a genetic small vessel disease.
• CADASIL is characterized by stroke, dementia, and migraine with aura, linked to Notch3 mutations.
• CADASIL mutations are known to cause cerebrovascular dysfunction.

Purpose of the Study:

• To investigate the impact of specific CADASIL mutations on ischemic stroke outcomes in a mouse model.
• To elucidate the underlying mechanisms contributing to increased stroke vulnerability in CADASIL.

Main Methods:

• Utilized transgenic mouse models carrying human CADASIL Notch3 mutations (R90C, R169C).
• Induced ischemic stroke using filament middle cerebral artery occlusion.
• Assessed infarct volume, neurological deficits, cerebral blood flow, and electrophysiological properties (spreading depolarizations).

Main Results:

• CADASIL mutant mice exhibited larger infarcts and worse neurological deficits post-stroke compared to wild-type mice.
• Mutants displayed a higher threshold of cerebral blood flow required to maintain tissue viability, indicating increased ischemic sensitivity.
• Increased frequency of peri-infarct spreading depolarizations and elevated extracellular K+ were observed in mutants, suggesting impaired K+ clearance.

Conclusions:

• Human CADASIL mutations exacerbate ischemic stroke outcomes by increasing brain tissue sensitivity to ischemia.
• Impaired extracellular ion homeostasis and heightened susceptibility to spreading depolarizations contribute to stroke vulnerability in CADASIL.
• These findings reveal a novel mechanism of enhanced ischemic injury in CADASIL, linked to ion dysregulation.