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Inhibition of Calcium-Sensing Receptor Alleviates Chronic Intermittent Hypoxia-Induced Cognitive Dysfunction via CaSR-PKC-ERK1/2 Pathway

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A Correction to this article was published on 23 March 2023

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Abstract

Obstructive sleep apnea–hypopnea syndrome (OSAHS) is typically characterized by chronic intermittent hypoxia (CIH), associated with cognitive dysfunction in children. Calcium-sensing receptor (CaSR) mediates the apoptosis of hippocampal neurons in various diseases. However, the effect of CaSR on OSAHS remains elusive. In the present study, we investigated the role of CaSR in CIH-induced memory dysfunction and underlying mechanisms on regulation of PKC-ERK1/2 signaling pathway in vivo and in vitro. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to cognitive dysfunction. CIH accelerated apoptosis of hippocampal neurons and resulted in the synaptic plasticity deficit via downregulated synaptophysin (Syn) protein level. The mice were intraperitoneally injected with CaSR inhibitor (NPS2143) 30 min before CIH exposure and the results demonstrated CaSR inhibitor alleviated the apoptosis and synaptic plasticity deficit in the hippocampus of CIH mice. We established intermittent hypoxia PC12 cell model and found that the activation of CaSR accelerated CIH-induced PC12 apoptosis and synaptic plasticity deficit by upregulated p-ERK1/2 and PKC. Overall, our findings revealed that CaSR held a critical function on CIH-induced cognitive dysfunction in mice by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity via augmenting CaSR-PKC-ERK1/2 pathway; otherwise, inhibition of CaSR alleviated CIH-induced cognitive dysfunction.

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Data Availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely thank the staff of the Department of Science and Research Center at the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University for their constant and unselfish help.

Funding

This work was supported by the Natural Science Foundation of China (81870073), Basic Public Welfare Projects of Zhejiang Province (Q23H010008), Medical Science and Technology Project of Zhejiang Province (2021KY209), and Science and Technology Plan Project of Wenzhou, China (Y20210009).

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  1. Huiya Ying, Zilong Zhang, and Wei Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Neurology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou, China

    Huiya Ying, Zilong Zhang, Zijing Yang, Cancan You & Xiucui Li

  2. Clinical Medicine, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China

    Huiya Ying, Zilong Zhang, Zijing Yang & Cancan You

  3. Department of Pediatric Orthopedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

    Wei Wang

  4. Department of Pediatric Sleep, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

    Yuanai Li & Xiaohong Cai

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Contributions

Xiucui Li, Wei Wang, and Xiaohong Cai participated in the research design. Huiya Ying, Zijing Yang, Yuanai Li, and Cancan You conducted the experiments and synthesized the data. Huiya Ying, Zilong Zhang, Xiucui Li, and Wei Wang contributed to the writing of the manuscript.

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Correspondence to Xiucui Li.

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Ying, H., Zhang, Z., Wang, W. et al. Inhibition of Calcium-Sensing Receptor Alleviates Chronic Intermittent Hypoxia-Induced Cognitive Dysfunction via CaSR-PKC-ERK1/2 Pathway. Mol Neurobiol 60, 2099–2115 (2023). https://doi.org/10.1007/s12035-022-03189-4

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