Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
Department of Anesthesiology, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
J Neurochem. 2018 May;145(4):287-298. doi: 10.1111/jnc.14307. Epub 2018 Feb 8.
Major depressive disorder is a common form of mental illness. Many brain regions are implicated in the pathophysiology and symptomatology of depression. Among key brain areas is the striatum that controls reward and mood and is involved in the development of core depression-like behavior in animal models of depression. While molecular mechanisms in this region underlying depression-related behavior are poorly understood, the glutamatergic input to the striatum is believed to play a role. In this study, we investigated changes in metabotropic glutamate (mGlu) receptor expression and signaling in the striatum of adult rats in response to prolonged (10-12 weeks) social isolation, a pre-validated animal paradigm modeling depression in adulthood. We found that mGlu5 receptor protein levels in the striatum were increased in rats that showed typical depression- and anxiety-like behavior after chronic social isolation. This increase in mGlu5 receptor expression was seen in both subdivisions of the striatum, the nucleus accumbens and caudate putamen. At subcellular and subsynaptic levels, mGlu5 receptor expression was elevated in surface membranes at synaptic sites. In striatal neurons, the mGlu5-associated phosphoinositide signaling pathway was augmented in its efficacy after prolonged social isolation. These data indicate that the mGlu5 receptor is a sensitive substrate of depression. Adulthood social isolation leads to the up-regulation of mGlu5 receptor expression and function in striatal neurons.
重度抑郁症是一种常见的精神疾病。许多大脑区域都与抑郁症的病理生理学和症状学有关。在关键的大脑区域中，纹状体控制着奖励和情绪，并且与抑郁症动物模型中核心抑郁样行为的发展有关。虽然该区域中与抑郁相关行为有关的分子机制尚不清楚，但纹状体中的谷氨酸能输入被认为发挥了作用。在这项研究中，我们研究了成年大鼠纹状体中代谢型谷氨酸 (mGlu) 受体表达和信号转导的变化，以响应长期（10-12 周）社交隔离，这是一种成熟动物模型中预验证的抑郁症模型。我们发现，在慢性社交隔离后表现出典型抑郁和焦虑样行为的大鼠中，纹状体中的 mGlu5 受体蛋白水平增加。这种 mGlu5 受体表达的增加见于纹状体的两个亚区，即伏隔核和尾壳核。在亚细胞和亚突触水平，mGlu5 受体在突触部位的表面膜中表达升高。在纹状体神经元中，mGlu5 相关的磷酸肌醇信号通路在长期社交隔离后其效力增强。这些数据表明，mGlu5 受体是抑郁症的敏感底物。成年社交隔离导致纹状体神经元中 mGlu5 受体表达和功能的上调。
