Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada.
Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy & Psychiatry, University of Calgary, Calgary, AB T2N4N1, Canada.
Neuron. 2015 Mar 18;85(6):1319-31. doi: 10.1016/j.neuron.2015.02.015. Epub 2015 Mar 5.
Collapse of endocannabinoid (eCB) signaling in the amygdala contributes to stress-induced anxiety, but the mechanisms of this effect remain unclear. eCB production is tied to the function of the glutamate receptor mGluR5, itself dependent on tyrosine phosphorylation. Herein, we identify a novel pathway linking eCB regulation of anxiety through phosphorylation of mGluR5. Mice lacking LMO4, an endogenous inhibitor of the tyrosine phosphatase PTP1B, display reduced mGluR5 phosphorylation, eCB signaling, and profound anxiety that is reversed by genetic or pharmacological suppression of amygdalar PTP1B. Chronically stressed mice exhibited elevated plasma corticosterone, decreased LMO4 palmitoylation, elevated PTP1B activity, reduced amygdalar eCB levels, and anxiety behaviors that were restored by PTP1B inhibition or by glucocorticoid receptor antagonism. Consistently, corticosterone decreased palmitoylation of LMO4 and its inhibition of PTP1B in neuronal cells. Collectively, these data reveal a stress-responsive corticosterone-LMO4-PTP1B-mGluR5 cascade that impairs amygdalar eCB signaling and contributes to the development of anxiety.
杏仁核内内源性大麻素（eCB）信号的崩溃导致应激诱导的焦虑，但这种效应的机制仍不清楚。eCB 的产生与谷氨酸受体 mGluR5 的功能有关，而 mGluR5 本身依赖于酪氨酸磷酸化。本文中，我们发现了一条通过 mGluR5 磷酸化将 eCB 调节焦虑联系起来的新途径。缺乏内源性酪氨酸磷酸酶 PTP1B 抑制剂 LMO4 的小鼠显示出 mGluR5 磷酸化、eCB 信号和明显的焦虑减少，而通过基因或药理学抑制杏仁核 PTP1B 可以逆转这种情况。慢性应激的小鼠表现出血浆皮质酮升高、LMO4 棕榈酰化减少、PTP1B 活性升高、杏仁核内 eCB 水平降低和焦虑行为，这些都可以通过 PTP1B 抑制或糖皮质激素受体拮抗作用得到恢复。一致地，皮质酮降低了神经元细胞中 LMO4 的棕榈酰化及其对 PTP1B 的抑制作用。总的来说，这些数据揭示了一个应激反应性的皮质酮-LMO4-PTP1B-mGluR5 级联反应，它损害了杏仁核内的 eCB 信号传递，并导致了焦虑的发展。
