Wagner Klaus V, Hartmann Jakob, Labermaier Christiana, Häusl Alexander S, Zhao Gengjing, Harbich Daniela, Schmid Bianca, Wang Xiao-Dong, Santarelli Sara, Kohl Christine, Gassen Nils C, Matosin Natalie, Schieven Marcel, Webhofer Christian, Turck Christoph W, Lindemann Lothar, Jaschke Georg, Wettstein Joseph G, Rein Theo, Müller Marianne B, Schmidt Mathias V
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
Neuropsychopharmacology. 2015 Mar 13;40(5):1222-33. doi: 10.1038/npp.2014.308.
Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.
应激诱导的精神疾病，如抑郁症，最近被认为与中枢神经系统中谷氨酸传递的变化有关。谷氨酸信号由一系列受体介导，包括代谢型谷氨酸受体（mGluRs）。特别是，mGluR亚型5（mGluR5）与应激诱导的精神病理学高度相关。主要的支架蛋白Homer1与mGluR5发生关键相互作用，并且也与多种精神病理学有关。然而，Homer1在这种情况下的具体作用仍知之甚少。我们使用慢性社会挫败应激作为抑郁症的既定动物模型，研究了Homer1a和Homer1b/c亚型的转录变化以及Homer1与mGluR5的功能偶联。接下来，我们研究了Homer1缺失、Homer1a过表达以及mGluR5反向激动剂CTEP（2-氯-4-（（2,5-二甲基-1-（4-（三氟甲氧基）苯基）-1H-咪唑-4-基）乙炔基）吡啶）的长期给药对慢性应激影响的后果。在暴露于慢性应激的小鼠中，Homer1b/c而非Homer1a的mRNA上调，因此Homer1/mGluR5偶联被破坏。我们发现在长期应激的Homer1基因敲除（KO）小鼠中存在明显的多动行为以及下丘脑-垂体-肾上腺轴活动失调。选择性且口服生物可利用的mGluR5反向激动剂CTEP的长期给药能够恢复慢性应激诱导的行为改变，而海马体中Homer1a的过表达导致对慢性应激的易感性增加，表现为对应激的生理反应增强以及抑郁样行为加剧。总体而言，我们的结果表明谷氨酸能系统与应激诱导的精神疾病的发生有关，并支持将Homer1/mGluR5复合物作为开发新型抗抑郁药的靶点。
