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The Two-Pore Domain Potassium Channel TREK-1 Promotes Blood–Brain Barrier Breakdown and Exacerbates Neuronal Death After Focal Cerebral Ischemia in Mice

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Abstract

Earlier studies have shown the neuroprotective role of TWIK-related K+ channel 1 (TREK-1) in global cerebral and spinal cord ischemia, while its function in focal cerebral ischemia has long been debated. This study used TREK-1-deficient mice to directly investigate the role of TREK-1 after focal cerebral ischemia. First, immunofluorescence assays in the mouse cerebral cortex indicated that TREK-1 expression was mostly abundant in astrocytes, neurons, and oligodendrocyte precursor cells but was low in myelinating oligodendrocytes, microglia, or endothelial cells. TREK-1 deficiency did not affect brain weight and morphology or the number of neurons, astrocytes, or microglia but did increase glial fibrillary acidic protein (GFAP) expression in astrocytes of the cerebral cortex. The anatomy of the major cerebral vasculature, number and structure of brain micro blood vessels, and blood–brain barrier integrity were unaltered. Next, mice underwent 60 min of focal cerebral ischemia and 72 h of reperfusion induced by the intraluminal suture method. TREK-1-deficient mice showed less neuronal death, smaller infarction size, milder blood–brain barrier (BBB) breakdown, reduced immune cell invasion, and better neurological function. Finally, the specific pharmacological inhibition of TREK-1 also decreased infarction size and improved neurological function. These results demonstrated that TREK-1 might play a detrimental rather than beneficial role in focal cerebral ischemia, and inhibition of TREK-1 would be a strategy to treat ischemic stroke in the clinic.

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Fig. 1

adapted from the whole genome RNA-sequencing transcriptome and splicing database of mouse cerebral cortex [52]. b Immunofluorescence revealed that TREK-1 protein was extensively expressed in neurons. Astrocytes (c) and OPCs (d) also highly expressed TREK-1, while mature oligodendrocytes or myelin sheaths (e) and microglia (f) seldom expressed TREK-1. In a few brain regions, TREK-1 was detected in endothelial cells (g) and SMCs (h). Interestingly, TREK-1 was also found in the choroid plexus (i). Scale bar = 20 μm in b–i

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Abbreviations

K2P:

Two-pore domain K channel

TWIK:

Tandem of pore domains in a weak inward rectifying K channel

TREK:

TWIK-related K channel

TRAAK:

TWIK-related arachidonic acid activated K channel

TASK:

TWIK-related acid sensitive K channel

BBB:

Blood–brain barrier

WT:

Wild type

KO:

Knockout

MMP-9:

Matrix metalloproteinase-9

ACA:

Anterior carotid artery

CCA:

Common carotid artery

ECA:

External carotid artery

ICA:

Internal carotid artery

MCA:

Middle cerebral artery

PCA:

Posterior cerebral artery

PCoA:

Posterior communicating artery

MCAO:

Middle cerebral artery occlusion

PCR:

Polymerase chain reaction

rCBF:

Relative cerebral blood flow

OPC:

Oligodendrocyte precursor cell

OGD:

Oxygen glucose deprivation

CNS:

Central nervous system

TBS:

Tris-buffered saline

PBS:

Phosphate buffered saline

TUNEL:

Terminal deoxynucleotidyl transferase-mediated nick end labeling

AQP4:

Aquaporin-4

EAE:

Experiment autoimmune encephalomyelitis

GFAP:

Glial filament acid protein

TJs:

Tight junctions

BMs:

Basement membranes

ROIs:

Region of interests

ICAM-1:

Intercellular adhesion molecule-1

PECAM-1:

Platelet endothelial cellular adhesion molecule-1

VCAM-1:

Vascular cell adhesion molecule-1

RRID:

Research resource identifiers

IF:

Immunofluorescence

WB:

Western blot

GFAP:

Glial fibrillary acidic protein

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Acknowledgements

We thank Dr. Min Zhou for gifting TREK-1 KO mice.

Funding

This study was supported by the National Natural Science Foundation of China (81501020, 81974180, 82001272) and Hubei Natural Science Foundation (2019CFB678).

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Authors and Affiliations

  1. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xiaolong Zheng, Zhou Zhu, Yongkang Fang, Yeye Tian, Minjie Xie, Wei Wang & Yang Liu

  2. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jun Yang

  3. Key Laboratory of Neurological Diseases of Chinese Ministry of Education, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Wei Wang

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  1. Xiaolong Zheng
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Contributions

Yang Liu, Minjie Xie, and Wei Wang conceived the study. Xiaolong Zheng, Yang Liu, Minjie Xie, and Wei Wang designed the experiments. Xiaolong Zheng and Jun Yang performed experiments. Zhou Zhu, Yongkang Fang, and Yeye Tian analyzed results. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Yang Liu.

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Ethics Approval

All animal experiments were performed under the protocol approved by the Committee on the Ethics of Animal Experiments and the Institutional Animal Care and Use Committee at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (ethics approval number, TJH-201908001).

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Supplementary file1 (DOCX 19 KB)

12035_2021_2702_MOESM2_ESM.pdf

Fig. S1 TREK-1 KO attenuated infarction in mice after focal cerebral ischemia. a, Body weight loss in male mice 72 hours after tMCAO, n=12 animals in the WT and KO groups. b, Normalized spleen weight ratio in male mice 72 hours after tMCAO, n=12 animals in the WT and KO groups. c, Survival curve of male mice 72 hours after tMCAO, n=12 animals in the WT and KO groups. d-f, edema area, edema volume and edema ratio in male mice, n=12 animals in the WT and KO groups. g-h, Infarct area and infarct volume in male mice, n=12 animals in the WT and KO groups. i, Representative images of CD3 staining in the infarct core of male mouse brain sections. j, Body weight loss in female mice 72 hours after tMCAO, n=6 animals in the WT and KO groups. k, Normalized spleen weight ratio in female mice 72 hours after tMCAO, n=6 animals in the WT and KO groups. l, Survival curve of female mice after tMCAO; n=6 animals in the WT and KO groups. m-o, Edema area, edema volume and edema ratio in female mice after tMCAO, n=6 animals in the WT and KO groups. p-q, Infarct area, infarct volume in female mice after tMCAO, n=12 animals in the WT and KO groups. Scale bar = 10 μm in i. (PDF 158 KB)

12035_2021_2702_MOESM3_ESM.pdf

Fig. S2 Pharmacological inhibition of TREK-1 attenuated infarction in mice after focal cerebral ischemia. a, Body weight loss in vehicle- and spadin-treated male mice 72 hours after tMCAO, n=10 animals in the vehicle group and 8 animals in the spadin group. b, Normalized spleen weight ratio, n=10 animals in the vehicle group and 8 animals in the spadin group. e, Survival curve of vehicle and spadin male mice, n=10 animals in the vehicle group and 8 animals in the spadin group. d-f, Edema area, edema volume and edema ratio between male vehicle and spadin mice; n=10 animals in the vehicle group and 8 animals in the spadin group. g-h, Infarct area and infarct volume between male vehicle and spadin mice, n=10 animals in the vehicle group and 8 animals in the spadin group. (PDF 114 KB)

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Zheng, X., Yang, J., Zhu, Z. et al. The Two-Pore Domain Potassium Channel TREK-1 Promotes Blood–Brain Barrier Breakdown and Exacerbates Neuronal Death After Focal Cerebral Ischemia in Mice. Mol Neurobiol 59, 2305–2327 (2022). https://doi.org/10.1007/s12035-021-02702-5

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