Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease

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Dokumenter

Minghuan Wang, Chuan Qin, Xiang Luo, Jie Wang, Xuxia Wang, Minjie Xie, Jing Hu, Jie Cao, Ting Hu, Steven A. Goldman, Maiken Nedergaard, Wei Wang

Rational: Myelin loss is a characteristic feature of both ischemic white matter disease and its associated vascular dementia, and is a hallmark of chronic cerebral hypoperfusion due to carotid artery stenosis. Yet the cellular mechanisms involved in ischemic dysmyelination are not well-understood, and no effective treatment has emerged to prevent or slow hypoperfusion-related demyelination. In a study employing the bilateral common carotid artery stenosis (BCAS) mouse model, we found reduced cerebral blood flow velocity and arteriolar pulsatility, and confirmed that prolonged BCAS provoked myelin disruption. These pathological features were associated with marked cognitive decline, in the absence of evident damage to axons. Methods: To assess the role of astroglial communication in BCAS-associated demyelination, we investigated the effect of deleting or inhibiting connexin 43 (Cx43), a constituent of astroglial gap junctions and hemichannels. Results: Genetic deletion and pharmacological inhibition of gap junctions both protected myelin integrity and rescued cognitive decline in the BCAS-treated mice. Gap junction inhibition also suppressed the transient increase in extracellular glutamate observed in the callosal white matter of wild-type mice exposed to BCAS. Conclusion: These findings suggest that astrocytic Cx43 may be a viable target for attenuating the demyelination and cognitive decline associated with chronic cerebral hypoperfusion.

OriginalsprogEngelsk
TidsskriftTheranostics
Vol/bind9
Udgave nummer15
Sider (fra-til)4474-4493
Antal sider20
ISSN1838-7640
DOI
StatusUdgivet - 2019

ID: 228250070