Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P R China.
Science. 2013 Aug 30;341(6149):1016-20. doi: 10.1126/science.1240729.
The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the β form of calcium/calmodulin-dependent protein kinase type II (βCaMΚΙΙ) was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing β-, but not α-, CaMKII in the LHb strongly enhanced the synaptic efficacy and spike output of LHb neurons and was sufficient to produce profound depressive symptoms, including anhedonia and behavioral despair. Down-regulation of βCaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify βCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression.
外侧缰核（LHb）最近已成为抑郁症病理生理学中的关键脑区。然而，LHb 在抑郁症中变得过度活跃的分子机制尚不清楚。通过定量蛋白质组学筛选，我们发现钙/钙调蛋白依赖性蛋白激酶 II 的β 形式（βCaMΚΙΙ）在抑郁症动物模型的 LHb 中表达显著上调，并被抗抑郁药下调。增加 LHb 中的β-CaMKII（而非α-CaMKII）强烈增强了 LHb 神经元的突触效能和尖峰输出，足以产生严重的抑郁症状，包括快感缺失和行为绝望。下调βCaMKII 水平、阻断其活性或其靶分子谷氨酸受体 GluR1 可逆转抑郁症状。这些结果表明βCaMKII 是 LHb 神经元功能的强大调节剂，也是抑郁症的关键分子决定因素。
