基于前额叶M1-Ach受体调控谷氨酸/γ-氨基丁酸平衡介导突触可塑性探讨针刺快速抗抑郁的机制

一线抗抑郁药起效延迟，目前，快速抗抑郁机制主要基于优化多靶点的单胺策略和谷氨酸（Glu）/γ-氨基丁酸（GABA）平衡调控突触可塑性的非单胺策略，而“拮抗前额叶神经元M1-Ach受体-Glu/GABA平衡-AMPA受体激活-BDNF释放-mTORC1通路激活-突触修复”是重要的非单胺策略之一。本团队前期研究提示：针刺能改善抑郁症状，其机制与促进Glu转运、增加BDNF含量及突触蛋白表达有关。预实验显示：针刺可快速起效，拮抗前额叶M1-Ach受体，并调控突触修复，而未改善单胺神经递质的含量。因此，本研究在前期研究基础上，以前额叶神经元M1-Ach受体调控Glu/GABA平衡介导突触可塑性为切入点。探寻针刺快速抗抑郁的起效时间；并运用受体抑制剂、激活剂和基因敲除等方法，应用膜片钳、高尔基染色和WB等技术探讨针刺拮抗前额叶M1-Ach受体对突触结构及功能可塑性作用，为针刺快速抗抑郁提供实验依据。

First-line antidepressant drug action is challenged by the delayed clinical onset. At present, there are two main mechanism of rapid antidepressant action. One is the monoaminergic strategy acting on multi-targets, and the other one is the non-monoaminergic strategy targeting the balance of glutamatergic (Glu) and γ-aminobutyric acid (GABA) and neuroplasticity. One of the antidepressant mechanisms in the non-monoaminergic strategy involved in the inhibition of type 1 muscarinic acetylcholine receptors (M1-AchRs) in the prefrontal cortex (PFC), resulting in the balance of Glu/GABA, the activation of AMPA receptor, BDNF release, the activation of mTORC1 signaling and synaptic plasticity. Our previous studies suggested that acupuncture could relieve depressive symptoms, and the antidepressant action was related to the increase in glutamatergic transmission, BDNF release and synaptic proteins. Our pre-experiments showed that acupuncture could ameliorate depressive behaviors rapidly in animal models, while it could antagonize the expression of M1-AchRs and restore synaptic injury in the PFC, but had no effect on monoamine neurotransmitters. Therefore, our present research will focus on the synaptic plasticity mediated by the antagonism of M1-AchRs in the PFC, and explore the onset time of acupuncture for rapid antidepressant action. We will use the antagonist/ agonist of M1-AchRs and gene knockouts technology, and techniques such as patch clamp, Golgi staining, and Western blot, to investigate the effects of acupuncture on synaptic structural and functional plasticity through antagonizing M1-AchRs in the PFC. It will provide experimental evidence for rapid antidepressant action of acupuncture.