Department of Psychiatry and Behavioral Sciences, The Asher Center for Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Biol Psychiatry. 2010 Dec 1;68(11):1007-15. doi: 10.1016/j.biopsych.2010.09.004.
Glutamatergic transmission is one of the main components of the stress response; nevertheless, its role in the emotional stress sequelae is not known. Here, we investigated whether interactions between group I metabotropic glutamate receptors (metabotropic glutamate receptor 1 and metabotropic glutamate receptor 5 [mGluR5]) and Homer proteins mediate the delayed and persistent enhancement of fear induced by acute stress.
Antagonists and inverse agonists of metabotropic glutamate receptor 1 and mGluR5 were injected into the hippocampus after immobilization stress and before contextual fear conditioning. Metabotropic glutamate receptor 5 was displaced from constitutive Homer scaffolds by viral transfection of Homer1a or injection of Tat decoy peptides. The effects of these manipulations on stress-enhanced fear were determined.
We show that stress induces interactions between hippocampal mGluR5 and Homer1a; causes a sustained, ligand-independent mGluR5 activity; and enhances contextual fear. Consistent with this mechanism, enhancement of fear was abolished by delayed poststress application of inverse agonists, but not antagonists, of mGluR5. The effect of stress was mimicked by virally transfected Homer1a or injection of Tat-metabotropic glutamate receptor C-tail decoy peptides into the hippocampus.
Constitutive activation of mGluR5 is identified as a principal hippocampal mechanism underlying the delayed stress effects on emotion and memory. Inverse agonists, but not antagonists, of mGluR5 are therefore proposed as a preventive treatment option for acute and posttraumatic stress disorders.
谷氨酸能传递是应激反应的主要组成部分之一；然而，其在情绪应激后遗症中的作用尚不清楚。在这里，我们研究了群体 I 代谢型谷氨酸受体（代谢型谷氨酸受体 1 和代谢型谷氨酸受体 5[mGluR5]）和 Homer 蛋白之间的相互作用是否介导急性应激引起的恐惧的延迟和持续增强。
在固定应激后和情景恐惧条件反射之前，将代谢型谷氨酸受体 1 和 mGluR5 的拮抗剂和反向激动剂注入海马体。通过 Homer1a 的病毒转染或 Tat 诱饵肽的注射将 mGluR5 从组成性 Homer 支架上置换出来。这些操作对应激增强的恐惧的影响。
我们表明，应激诱导海马 mGluR5 与 Homer1a 之间的相互作用；引起持续的、配体非依赖性的 mGluR5 活性；并增强情景恐惧。与该机制一致，延迟的应激后应用 mGluR5 的反向激动剂而非拮抗剂可消除恐惧的增强。通过病毒转染 Homer1a 或向海马体注射 Tat-代谢型谷氨酸受体 C 末端诱饵肽模拟应激的作用。
鉴定出组成型激活 mGluR5 是海马体介导应激对情绪和记忆的延迟效应的主要机制。因此，mGluR5 的反向激动剂而非拮抗剂被提议作为急性和创伤后应激障碍的预防治疗选择。
