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Inactivation of ERK1/2-CREB Pathway Is Implicated in MK801-induced Cognitive Impairment

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Abstract

Objective

Schizophrenia (SZ) is associated with cognitive impairment, and it is known that the activity of cAMP response element binding protein (CREB) decreases in the brain of SZ patients. The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit. The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.

Methods

MK-801 was used to induce SZ in rats. Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats. The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment, respectively.

Results

The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats. Interestingly, among the upstream kinases of CREB, merely ERK1/2 was downregulated, while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats. The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133, and induced synaptic dysfunction in primary hippocampal neurons. Conversely, the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.

Conclusion

These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment. The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.

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Acknowledgements

We would like to express our gratitude and appreciation to Dan KE and Qun WANG for their expertise and technical assistance. We also thank all members of the research team for the constructive discussion and suggestions that shaped this work.

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Author notes

  1. The authors contributed equally to this work.

Authors and Affiliations

  1. Central Laboratory, Scientific Research Department, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Cui-ping Guo & Xiang Gao

  2. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China

    Cui-ping Guo, Jian-zhi Wang & Xiao-chuan Wang

  3. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Cui-ping Guo, Wen-sheng Li, Yi Liu, Yacoubou Abdoul Razak Mahaman, Bin Zhang, Jian-zhi Wang, Rong Liu, Hong-lian Li & Xiao-chuan Wang

  4. Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China

    Xiao-chuan Wang

Authors
  1. Cui-ping Guo
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  2. Wen-sheng Li
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  9. Xiao-chuan Wang
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Correspondence to Xiao-chuan Wang or Xiang Gao.

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The authors declare that they have no conflicts of interest.

Author Jian-zhi WANG is a member of the Editorial Board for Current Medical Science. The paper was handled by other editors and has undergone rigorous peer review process. Author Jian-zhi WANG was not involved in the journal’s review of, or decisions related to, this manuscript.

Additional information

This work was supported in part by grants from National Natural Science Foundation of China (No. 31929002, No. 82201326 No. 82071440 and No. 92049107), Science, Technology and Innovation Commission of Shenzhen Municipality (No. JCYJ20210324141405014), Guangdong Basic and Applied Basic Research Foundation (No. 2020B1515120017) and the Academic Frontier Youth Team Project to Xiao-chuan WANG from Huazhong University of Science and Technology.

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Guo, Cp., Li, Ws., Liu, Y. et al. Inactivation of ERK1/2-CREB Pathway Is Implicated in MK801-induced Cognitive Impairment. CURR MED SCI 43, 13–21 (2023). https://doi.org/10.1007/s11596-022-2690-5

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  • DOI: https://doi.org/10.1007/s11596-022-2690-5

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