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Connexin 43 Promotes Neurogenesis via Regulating Aquaporin-4 after Cerebral Ischemia

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A Correction to this article was published on 30 April 2024

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Abstract

We aimed to test the effects of connexin43 (Cx43) on ischemic neurogenesis and examined whether it was dependent on aquaporin-4 (AQP4). We detected the expression of Cx43 and AQP4 in the ipsilateral subventricular zone (SVZ) and peri-infarct cortex after middle cerebral artery occlusion (MCAO). Also, we examined neurogenesis in the above regions via co-labeling of 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclear antigen (NeuN) and BrdU/doublecortin (DCX). The effects of Cx43 and AQP4 were investigated by using two transgenic animals: heterozygous Cx43 (Cx43±) mice and AQP4 knockout (AQP4−/−) mice, and connexin mimetic peptide (CMP), a selective Cx43 blocker. We demonstrated AQP4 and Cx43 were co-expressed in the astrocytes after MCAO and the expression was highly increased in ipsilateral SVZ and peri-infarct cortex. Cx43± mice had larger infarction volumes and worse neurological function. Both BrdU/NeuN and BrdU/DCX co-labeled cells in the two regions were reduced in Cx43± and AQP4−/− mice compared to wild-type (WT) mice, suggesting Cx43 and AQP4 participated in neurogenesis of neural stem cells. Moreover, CMP decreased AQP4 expression and inhibited neurogenesis in WT mice, while the latter failed to be observed in AQP4−/− mice. Besides, higher levels of IL-1β and TNF-α were detected in the SVZ and peri-infarct cortex of AQP4−/− and Cx43± mice than those in WT mice. In conclusion, our data suggest that Cx43 elicits neuroprotective effects after cerebral ischemia through promoting neurogenesis in the SVZ to regenerate the injured neurons, which is AQP4 dependent and associated with down-regulation of inflammatory cytokines IL-1β and TNF-α.

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

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Funding

This research was supported by grants from the National Natural Science Foundation of China (nos. 81500998, 81901102, and 82071472).

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Authors and Affiliations

  1. Department of Gerontology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, 200233, Shanghai, China

    Heling Chu & Qihao Guo

  2. Department of Internal Neurology, Qingdao Municipal Hospital, Qingdao, China

    Jing Dong

  3. Department of Neurology, Huashan Hospital, Fudan University, No. 12 Mid. Wulumuqi Road, Shanghai, 200040, China

    Yuping Tang

  4. Health Management Center, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, No. 160 Pujian Road, Shanghai, 200120, China

    Chuyi Huang

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Contributions

HC and JD: study design, experiment performance, and analysis and drafting of the manuscript. YT, CH, and QG: conception and design and revision and approval of the manuscript. All authors gave final approval of the version to be published.

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Correspondence to Yuping Tang, Chuyi Huang or Qihao Guo.

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Our animal studies and protocol were approved by the Institutional Animal Care and Use Committee of Fudan University.

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Chu, H., Dong, J., Tang, Y. et al. Connexin 43 Promotes Neurogenesis via Regulating Aquaporin-4 after Cerebral Ischemia. Neurotox Res 41, 349–361 (2023). https://doi.org/10.1007/s12640-023-00646-3

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