State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Neuropsychopharmacology. 2012 Apr;37(5):1305-20. doi: 10.1038/npp.2011.319. Epub 2011 Dec 21.
Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.
越来越多的证据表明胶质细胞异常与重度抑郁症（MDD）的病理生理学有关。缝隙连接通讯是星形胶质细胞功能的主要决定因素。然而，缝隙连接功能障碍是否参与 MDD 的发展尚不清楚。本研究探讨了慢性不可预测应激（CUS）后大鼠前额叶皮质（PFC）星形胶质细胞缝隙连接功能的变化，CUS 是一种抑郁的啮齿动物模型。暴露于 CUS 并在蔗糖偏好测试（SPT）和新奇抑制进食测试（NSFT）中表现出行为缺陷的动物表现出缝隙连接通道通透性染料扩散和连接蛋白 43（Cx43）表达的显著降低，Cx43 是星形胶质细胞缝隙连接的主要成分，以及 PFC 中异常的缝隙连接超微结构。此外，我们分析了典型抗抑郁药氟西汀和度洛西汀以及糖皮质激素受体（GR）拮抗剂米非司酮对 CUS 诱导的缝隙连接功能障碍和抑郁样行为的影响。CUS 诱导的细胞和行为改变可被典型抗抑郁药或米非司酮逆转和/或阻断，表明其抗抑郁作用机制可能涉及改善缝隙连接功能障碍，细胞变化可能与 GR 激活有关。然后，我们研究了 PFC 中药理学缝隙连接阻断对抑郁样行为的影响。结果表明，卡波酮（CBX）输注在 SPT 中诱导快感缺失，在 NSFT 中诱导焦虑，Cx43 模拟肽 Gap27 和 Gap26 也诱导快感缺失，这是抑郁症的核心症状。总之，这项研究支持了缝隙连接功能障碍导致抑郁症发病机制的假说。
