PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice.
PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice.
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DOI：
10.1172/jci165812
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发表时间：
2023-09-15
影响因子：
15.9
通讯作者：
Liu, Shuibing
中科院分区：
文献类型：
--
作者：
Wang, Xinshang;Jiang, Yongli;Feng, Ban;Ma, Xue;Zhang, Kun;Yang, Fan;Liu, Zhenguo;Yang, Le;Yue, Jiao;Lu, Liang;Song, Dake;Guo, Qingjuan;Qi, Jingyu;Li, Xubo;Wang, Min;Zhang, Huinan;Huang, Jing;Zhao, Minggao;Liu, Shuibing
激素替代疗法（HRT）不推荐用于治疗绝经期妇女的学习和记忆衰退，因为它通过激活经典的雌激素受体ERα和ERβ产生不良反应。据报道，膜雌激素受体G蛋白偶联受体30（GPR 30）参与记忆调节;然而，其潜在机制知之甚少。在这里，我们发现GPR 30在星形胶质细胞中的缺失，而不是在神经元中，会损害雌性小鼠的学习和记忆。星形胶质细胞GPR 30耗竭诱导A1表型转变，损害神经元功能。进一步的研究表明，Praja 1（PJA 1），一种RING泛素连接酶，通过与Serpina 3 n结合介导星形胶质细胞GPR 30对学习和记忆的影响，Serpina 3 n是星形胶质细胞中神经炎症的分子标志物。在培养的小鼠和人星形胶质细胞中，GPR 30通过CREB信号通路正向调节PJA 1表达。此外，GPR 30和PJA 1的mRNA水平在从绝经后妇女分离的外来体中降低，而血浆中Serpina 3 n水平增加。总之，我们的研究结果表明星形胶质细胞GPR 30在雌性小鼠的学习和记忆能力中起着关键作用，并将GPR 30/PJA 1/Serpina 3 n确定为绝经后和绝经后妇女学习和记忆丧失的潜在治疗靶点。
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.
影响因子：
1.9
作者：
Frick, Karyn M.
通讯作者：
Frick, Karyn M.