Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China.
Behav Brain Res. 2019 May 17;364:50-61. doi: 10.1016/j.bbr.2019.02.014. Epub 2019 Feb 10.
Estrogens have been shown to play profound roles in the regulation of the structure and function of the hippocampus; however, the underlying mechanism is not clear. Previous studies have shown that when Rictor, the core component of the mammalian target of the rapamycin complex 2 (mTORC2), was deleted, hippocampal actin polymerization was reduced and long-term memory was seriously impaired. Although hippocampal Rictor could be regulated by estrogen receptor agonists/antagonists, whether Rictor could directly mediate estrogenic regulation of neuronal plasticity, spatial learning and memory remains unclear. In this study, we first examined the regulation of hippocampal Rictor and P-AKTser473 (P-AKT) by E2, then we used Rictor-specific dsRNA (shRictor) injected into the hippocampi of E2-treated ovariectomized (OVX) mice or into cultured cells. The results showed that both Rictor and P-AKT could be regulated by E2. OVX induced actin depolymerization, decreases in CA1 spine density and synapse density as well as changes in synaptic proteins were reversed by E2 replacement. However, these E2-mediated effects were significantly blocked by shRictor treatment. Similar results were also demonstrated by in vitro cell culture studies using E2 and/or shRictor. Importantly, we found that E2 replacement induced improvements in learning and memory impairment seen in OVX mice were significantly blocked by shRictor. Taken together, the current studies provided the first direct evidence for the important role of Rictor in estrogenic action on the hippocampus, indicating that it may be a therapeutic target for the treatment of E2-related, hippocampus-dependent cognitive dysfunction.
雌激素在调节海马体的结构和功能方面发挥着深远的作用；然而，其潜在机制尚不清楚。先前的研究表明，当雷帕霉素复合物 2（mTORC2）的核心组成部分 Rictor 被删除时，海马体中的肌动蛋白聚合减少，长期记忆严重受损。尽管海马体中的 Rictor 可以被雌激素受体激动剂/拮抗剂调节，但 Rictor 是否可以直接介导雌激素对神经元可塑性、空间学习和记忆的调节仍不清楚。在这项研究中，我们首先检查了 E2 对海马体 Rictor 和 P-AKTser473（P-AKT）的调节，然后使用特异性针对 Rictor 的 dsRNA（shRictor）注射到 E2 处理的去卵巢（OVX）小鼠或培养细胞的海马体中。结果表明，E2 可以调节 Rictor 和 P-AKT。OVX 诱导的肌动蛋白解聚、CA1 棘突密度和突触密度降低以及突触蛋白变化，均可被 E2 替代所逆转。然而，这些 E2 介导的效应被 shRictor 处理显著阻断。使用 E2 和/或 shRictor 的体外细胞培养研究也得到了类似的结果。重要的是，我们发现 E2 替代诱导的 OVX 小鼠学习和记忆障碍的改善被 shRictor 显著阻断。总之，目前的研究为 Rictor 在雌激素对海马体作用中的重要作用提供了直接证据，表明它可能是治疗与 E2 相关的、以海马体依赖的认知功能障碍的治疗靶点。
