氯胺酮快速抗抑郁的潜在靶点和神经微环路机制研究

Ketamine, a commonly used anesthetics in clinical practice, has been found to have rapid-onset and sustained antidepressant effects recently. The mechanism studies of ketamine is a research hotspot in depression treatment field. Ketamine, a multi-target drug, can act on NMDA/AMPA/GABA receptors and various ion channels. Studies showed that ketamine promotes the synaptic plasticity in medial prefrontal cortex (mPFC), which was correlated with the antidepressant effects of ketamine. However, the specific binding targets and the neural microcircuits mechanism in mPFC of ketamine are still unclear. mPFC dominates cognitive, decision-making, behavioral inhibition, emotional control, and many other advanced features. And "excitation-inhibition" microcircuits of mPFC plays an important role in neural development and pathogenesis of depression. Our preliminary data shows LZ01, the NMDARs partial antagonist can activate BDNF/mTOR signaling pathway and enhance synaptic plasticity in mPFC, evokes antidepressant effects in animals consequently. Therefore, in this study, by using optogenetic, electrophysiology and so on,we aim to elucidate two scientific questions: 1. Clarify the action target of ketamine relating to its rapid antidepressant effect. 2. Explore the neural microcircuits mechanisms of rapid antidepressant effect of ketamine on the neural microcircuits in mPFC. The purpose of this project is to illuminate the rapid-onset antidepressant mechanisms of ketamine, which will provide more theoretical basis for clinical practice and discovery of rapid-onset antidepressants.

近年来研究发现常用麻醉药氯胺酮具有快速和持久的抗抑郁作用，使其成为抑郁症治疗的热点。氯胺酮为多靶点药物，可作用于NMDA/AMPA/GABA受体及多种离子通道，已有研究显示氯胺酮抗抑郁作用与增强前额叶皮质（mPFC）兴奋性突触传递功能有关，但是具体作用靶点以及在mPFC神经微环路中的调控机制仍不清楚。mPFC是主导认知、决策和情绪调控等多种功能的高级中枢，其“兴奋-抑制”微环路功能紊乱与抑郁症发病密切相关。课题组前期已证实NMDA受体部分拮抗剂LZ01可在mPFC激活BDNF/mTOR信号通路并增强突触可塑性，继而产生抗抑郁作用。因此本课题组将结合光遗传、电生理等技术，重点阐述相关核心问题：1.氯胺酮快速抗抑郁的潜在靶点；2.氯胺酮快速抗抑郁的前额叶神经微环路机制。本研究旨在探明氯胺酮的快速抗抑郁作用的详细机制，为快速抗抑郁药物的研发和抑郁症的临床诊疗提供理论依据。

抑郁症发病率高社会危害大，临床一线抗抑郁药物普遍起效缓慢，疗效不确切，因此深入探明抑郁症的病因机制及研发快速起效，毒副作用小的抗抑郁药物有重要临床意义。近年来研究发现常用麻醉药氯胺酮具有快速和持久的抗抑郁作用，使其成为抑郁症治疗的热点。本项目围绕氯胺酮及其代谢产物（R-HNK）的快速抗抑郁靶点和内侧前额叶（mPFC）神经微环路功能机制开展了系统研究。并拓展性地开展了抗抑郁活性物质（如：一氧化二氮、催产素）的作用机理和吗啡戒断诱导抑郁样行为的病因机制。研究确证了中间神经元特异性分布的NMDA受体亚基NR2D在氯胺酮快速抗抑郁中有关键作用； R-HNK对TREK-1双孔钾离子通道有明显抑制作用；证明氯胺酮可增强mPFC兴奋性突触传递功能和产生快速抗抑郁作用，而这些过程依赖于mPFC抑制性突触传递功能的完整性。拓展性研究方面：阐明了一氧化二氮的快速抗抑郁机制与其激活mPFC nNOS信号通路相关；阐明了催产素对mPFC多巴胺能突触传递功能有明显增强作用，进而发挥抗抑郁作用；揭示了吗啡戒断增强杏仁核kappa受体功能介导慢性吗啡戒断引起的抑郁样行为。本项目研究成果为快速抗抑郁药物的研发和抑郁症的临床诊疗策略提供理论依据。