抑郁致病基因βCaMKII在生理、病理和药理状态下的表达调控机制

Major depression disorder is one of the most common psychiatric disorders today, imposing tremendous mental, physical, and economic burdens onto individual patients and society as a whole. Recently our lab discovered that over-expression of Ca2+/calmodulin-dependent kinase II B (βCaMKII) in lateral habenula causes core depression behaviors in animals, strongly suggesting that regulation on βCaMKII expression may be key to understand the molecular etiology of depression. Therefore we propose a systematic interrogation on the regulatory mechanisms of βCaMKII expression in habenula under physiological, pathological and pharmacological conditions. We will first investigate the roles of epigenetic, transcriptional and protein homeostatic (synthesis and degradation) mechanisms and their key regulators on βCaMKII expression and depression behaviors. Next we will identify changes in such regulatory mechanisms in pathological (i.e. depression) habenula, and determine whether such changes are sufficient to cause core depression behaviors. Finally we will study antidepressant’s impacts on βCaMKII expression and its regulatory pathways. Collectively, our investigation will not only identify the key mechanisms and factors that critically regulate βCaMKII levels in habenula, it will also discover changes in such mechanisms that significantly contribute to depression etiology. Lastly it will further provide new insights into the pharmacology of traditional antidepressants, and present novel targets for future drug development.

抑郁症是当今最常见的心理疾病之一，在心理、生理和经济上给患者个人和社会带来巨大的负担。本课题组近期发现βCaMKII基因外侧缰核中的过量表达能够在动物中导致核心抑郁症状，强烈指出βCaMKII表达水平的调控在抑郁症分子病理学中的重要性。因此我们提出系统地研究βCaMKII在生理，病理和药理状态下在缰核中的表达调控机制。我们将首先研究表观遗传学、转录调控和蛋白质合成与降解机制及其关键调控因子在βCaMKII调控和抑郁行为中的功能。下一步我们将研究这些调控通路在抑郁缰核中的变化，并确定这些变化是否能够导致抑郁表型。最后我们还将研究抗抑郁药物对βCaMKII表达和调控通路的影响。综合我们的研究，我们不仅能够发现对βCaMKII的表达具有关键调控作用的机制和因子，我们还揭示这些通路的变化能否导致抑郁，并最终进一步揭示传统抗抑郁药的药理机制，并为开发新药提供作用靶点。

本基金研究了βCaMKII在外侧缰核中表达水平的分子调控机制，证明DNA甲基化和NEDD4介导的蛋白质降解通路均不影响βCaMKII的转录和翻译产物的水平，提示对βCaMKII的表达调控应通过其他未知通路进行。在功能上，我们发现在小鼠外侧缰核中过量表达βCaMKII会上调缰核的神经活性，并直接诱发包括行为绝望和快感缺失在内的典型抑郁行为，而多种抗抑郁化合物可以有效逆转上述抑郁行为。在小鼠外侧缰核中敲除βCaMKII的表达，或使用βCaMKII特有的抑制剂KN92抑制其活性，都能够缓解由慢性束缚导致的典型抑郁行为；而抗抑郁化合物ketamine能在体外培养的神经细胞中直接下调βCaMKII的表达水平。以上结果都提示βCaMKII过量表达于缰核中可能导致抑郁症，而在缰核中抑制其活性或下调其表达水平可能是潜在的有效抗抑郁机制。