Paik Institute for Clinical Research, Inje University, Busan 47392, Korea.
Department of Psychiatry, Inje University Haeundae Paik Hospital, College of Medicine, Inje University, Busan 48108, Korea.
Int J Mol Sci. 2022 Jun 8;23(12):6416. doi: 10.3390/ijms23126416.
In several rodent models, acute administration of the metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist LY341495 induced antidepressant-like effects via a mechanism of action similar to that of ketamine. However, the effects of chronic mGlu2/3 antagonism have not yet been explored. Therefore, we investigated the effects of chronic LY341495 treatment on the mechanistic target of rapamycin complex 1 (mTORC1) signaling and the levels of synaptic proteins in mice subjected to chronic unpredictable stress (CUS). LY341495 (1 mg/kg) was administered daily for 4 weeks to mice with and without CUS exposure. After the final treatment, the forced swimming test (FST) was used to assess antidepressant-like effects. The hippocampal levels of mTORC1-related proteins were derived by Western blotting. Chronic LY341495 treatment reversed the CUS-induced behavioral effects of FST. CUS significantly reduced the phosphorylation of mTORC1 and downstream effectors [eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP-1) and small ribosomal protein 6 (S6)], as well as the expression of synaptic proteins postsynaptic density-95 (PSD-95) and AMPA receptor subunit GluR1 (GluA1) in the hippocampus. However, chronic LY341495 treatment rescued these deficits. Our results suggest that the activation of hippocampal mTORC1 signaling is related to the antidepressant effect of chronic LY341495 treatment in an animal model of CUS-induced depression.
在几种啮齿动物模型中，急性给予代谢型谷氨酸 2/3（mGlu2/3）受体拮抗剂 LY341495 可通过类似于氯胺酮的作用机制诱导抗抑郁样效应。然而，慢性 mGlu2/3 拮抗作用的影响尚未得到探索。因此，我们研究了慢性 LY341495 治疗对机械靶标雷帕霉素复合物 1（mTORC1）信号和慢性不可预测应激（CUS）暴露的小鼠突触蛋白水平的影响。LY341495（1mg/kg）每天给予小鼠 4 周，有或没有 CUS 暴露。最后一次治疗后，通过强迫游泳试验（FST）评估抗抑郁样效应。通过 Western blot 测定海马体中与 mTORC1 相关的蛋白水平。慢性 LY341495 治疗逆转了 CUS 诱导的 FST 行为效应。CUS 显著降低了 mTORC1 及其下游效应物（真核翻译起始因子 4E 结合蛋白 1（4E-BP-1）和小核糖体蛋白 6（S6））的磷酸化，以及突触后密度-95（PSD-95）和 AMPA 受体亚基 GluR1（GluA1）在海马体中的表达。然而，慢性 LY341495 治疗挽救了这些缺陷。我们的结果表明，海马体 mTORC1 信号的激活与慢性 LY341495 治疗在 CUS 诱导的抑郁动物模型中的抗抑郁作用有关。
