Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease

TY - JOUR

T1 - Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease

AU - Wang, Minghuan

AU - Qin, Chuan

AU - Luo, Xiang

AU - Wang, Jie

AU - Wang, Xuxia

AU - Xie, Minjie

AU - Hu, Jing

AU - Cao, Jie

AU - Hu, Ting

AU - Goldman, Steven A.

AU - Nedergaard, Maiken

AU - Wang, Wei

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Astrocyte

KW - Connexin 43

KW - Ischemic white matter disease

KW - Myelin injury

U2 - 10.7150/thno.31942

DO - 10.7150/thno.31942

M3 - Journal article

C2 - 31285774

AN - SCOPUS:85069288583

SN - 1838-7640

VL - 9

SP - 4474

EP - 4493

JO - Theranostics

JF - Theranostics

IS - 15

ER -