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PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice.

Author information

Affiliations

  • 1. Department of Pharmacology, School of Pharmacy and.
      Authors
    • Wang X 1
    • Feng B 1
    • Ma X 1
    • Zhang K 1
    • Yang F 1
    • Yue J 1
    • Lu L 1
    • Song D 1
    • Guo Q 1
    • Qi J 1
    • Li X 1
    • Wang M 1
    • Liu S 1
    (13 authors)
  • 2. Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
      Authors
    • Jiang Y 2
    • Yang L 2
    • Zhao M 2
    (3 authors)
  • 3. Department of Pharmacy, Northwest Women's and Children's Hospital, Xi'an, China.
      Authors
    • Liu Z 3
    (1 author)
  • 4. Department of Health Management, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
      Authors
    • Zhang H 4
    • Huang J 4
    (2 authors)

The Journal of Clinical Investigation, 15 Sep 2023, 133(18):e165812
https://doi.org/10.1172/jci165812 PMID: 37712419 PMCID: PMC10503807

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Abstract 

Hormone replacement therapy (HRT) is not recommended for treating learning and memory decline in menopausal women because it exerts adverse effects by activating classic estrogen receptors ERα and ERβ. The membrane estrogen receptor G protein-coupled receptor 30 (GPR30) has been reported to be involved in memory modulation; however, the underlying mechanisms are poorly understood. Here, we found that GPR30 deletion in astrocytes, but not in neurons, impaired learning and memory in female mice. Astrocytic GPR30 depletion induced A1 phenotype transition, impairing neuronal function. Further exploration revealed that Praja1 (PJA1), a RING ubiquitin ligase, mediated the effects of astrocytic GPR30 on learning and memory by binding to Serpina3n, which is a molecular marker of neuroinflammation in astrocytes. GPR30 positively modulated PJA1 expression through the CREB signaling pathway in cultured murine and human astrocytes. Additionally, the mRNA levels of GPR30 and PJA1 were reduced in exosomes isolated from postmenopausal women while Serpina3n levels were increased in the plasma. Together, our findings suggest a key role for astrocytic GPR30 in the learning and memory abilities of female mice and identify GPR30/PJA1/Serpina3n as potential therapeutic targets for learning and memory loss in peri- and postmenopausal women.

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Read article at publisher's site: https://doi.org/10.1172/jci165812

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    Funding 

    Funders who supported this work.

    National Natural Science Foundation of China (1)

    • Grant ID: 82071474,82003734,81771420,31972902

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    Natural Science Basic Research Program of Shaanxi Province (1)

    • Grant ID: 2022JQ-869

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    Scientific and Technological Innovation Team of Shaanxi Province (1)

    • Grant ID: 2023-CX-TD-63

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    Youth Talent Promotion Program of Shaanxi Association for Science and Technology (1)

    • Grant ID: 20210306

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