Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Tongji-Wisconsin Stem Cell Application Technology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Dec 20;95:109682. doi: 10.1016/j.pnpbp.2019.109682. Epub 2019 Jun 29.
Glutamatergic dysregulation has served as one common pathophysiology of major depressive disorder (MDD) and a promising target for treatment intervention. Previous studies implicate neurotransmission via metabotropic glutamate receptors (mGluRs) and Homer1 in stress-induced anhedonia, but the mechanisms have not been well elucidated. In the present study, we used two different animal models of depression, chronic social defeat stress (CSDS) and chronic restraint stress (CRS), to investigate the expression of Homer1 isoforms and functional interaction with mGluRs. We found that chronic stress selectively upregulated the expression of Homer1b/c in the hippocampus, whereas the level of Homer1a was unchanged. Additionally, there was a significant negative correlation between the levels of Homer1-mGluR5 signaling and depressive-like behaviors. Both application of paired-pulse low-frequency stimulation (PP-LFS) and the selective group 1 mGluRs agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) significantly enhanced mGluR-dependent long-term depression (LTD) at CA3-CA1 pyramidal cell synapses in slices from susceptible mice, whereas there was no change in NMDAR-dependent LTD induced by LFS. Furthermore, these effects were associated with the internalization of surface AMPARs in hippocampal pyramidal neurons, including reduced the expression of AMPARs and amplitude of AMPARs-mediated mEPSC. Finally, we found that chronic stress activated the KR-like ER kinase-eukaryotic initiation factor 2α (PERK-eIF2α) signaling pathway, subsequently phosphorylated cAMP response element binding protein (CREB) at the S129 and reduced the BDNF level, eventually leading to the impairment of synaptic transmission and depressive-like behaviors. Therefore, our study suggests that PERK-eIF2α acts as a critical target downstream of Homer1-mGluR5 complex to mediate chronic stress-induced depressive-like behaviors, and highlights them as a potential target for the treatment of mood disorder.
谷氨酸能调节紊乱被认为是重度抑郁症（MDD）的一种常见病理生理学机制，也是治疗干预的一个有前途的靶点。先前的研究表明，代谢型谷氨酸受体（mGluRs）和 Homer1 的神经传递与应激诱导的快感缺失有关，但这些机制尚未得到很好的阐明。在本研究中，我们使用了两种不同的抑郁动物模型，慢性社交挫败应激（CSDS）和慢性束缚应激（CRS），来研究 Homer1 同工型的表达及其与 mGluRs 的功能相互作用。我们发现，慢性应激选择性地上调了海马中 Homer1b/c 的表达，而 Homer1a 的水平没有变化。此外，Homer1-mGluR5 信号与抑郁样行为之间存在显著的负相关。成对脉冲低频刺激（PP-LFS）和选择性的 mGluR1 激动剂（RS）-3,5-二羟基苯甘氨酸（DHPG）的应用都显著增强了易感小鼠切片中海马 CA3-CA1 锥体神经元突触中 mGluR 依赖性长时程抑制（LTD），而 LFS 诱导的 NMDAR 依赖性 LTD 没有变化。此外，这些效应与海马锥体神经元表面 AMPAR 的内化有关，包括 AMPAR 表达和 AMPAR 介导的 mEPSC 幅度的减少。最后，我们发现慢性应激激活了 KR 样内质网激酶-真核起始因子 2α（PERK-eIF2α）信号通路，随后磷酸化 cAMP 反应元件结合蛋白（CREB）的 S129 位并降低了 BDNF 水平，最终导致突触传递和抑郁样行为的损伤。因此，我们的研究表明，PERK-eIF2α 作为 Homer1-mGluR5 复合物下游的关键靶点，介导慢性应激诱导的抑郁样行为，并强调其作为治疗情绪障碍的潜在靶点。
