BACKGROUND Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology and treatment of depression. Recent clinical studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in patients with depression. Rodent studies demonstrate that scopolamine increases glutamate transmission and synaptogenesis in the medial prefrontal cortex (mPFC). Here we tested the hypothesis that activity-dependent BDNF release within the mPFC is necessary for the antidepressant actions of scopolamine. METHODS Behavioral effects of scopolamine were assessed in BDNF Val/Met knock-in mice, in which BDNF processing and release are impaired. In addition, intra-mPFC infusion of a BDNF-neutralizing antibody was performed to test the necessity of BDNF release in driving scopolamine-induced behavioral responses. Further in vivo and in vitro experiments were performed to delineate BDNF-dependent mechanisms underlying the effects of scopolamine. RESULTS We found that BDNF Met/Met mice have attenuated responses to scopolamine and that anti-BDNF antibody infusions into the mPFC prevented the antidepressant-like behavioral effects of scopolamine. In vitro experiments show that scopolamine rapidly stimulates BDNF release and tropomyosin receptor kinase B-extracellular signal-regulated kinase signaling. Moreover, these effects require alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor activation and are blocked by neuronal silencing. Importantly, pretreatment with verapamil prevented scopolamine-induced behavioral responses and BDNF-tropomyosin receptor kinase B signaling, suggesting that these effects are dependent on activation of voltage-dependent calcium channels. CONCLUSIONS The results identify an essential role for activity-dependent BDNF release in the rapid antidepressant effects of scopolamine. Attenuation of responses in BDNF Met mice indicates that patients with the Met allele may be less responsive to scopolamine.

中文翻译：

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东莨菪碱的快速抗抑郁作用需要活动依赖性脑源性神经营养因子释放

背景脑源性神经营养因子（BDNF）在抑郁症的病理生理学和治疗中起关键作用。最近的临床研究表明东莨菪碱是一种非选择性毒蕈碱乙酰胆碱受体拮抗剂，可对抑郁症患者产生快速的抗抑郁作用。啮齿动物研究表明东莨菪碱增加内侧前额叶皮层 (mPFC) 的谷氨酸传递和突触发生。在这里，我们测试了一个假设，即 mPFC 内的活性依赖性 BDNF 释放是东莨菪碱的抗抑郁作用所必需的。方法 在 BDNF Val/Met 敲入小鼠中评估东莨菪碱的行为影响，其中 BDNF 加工和释放受损。此外，进行 BDNF 中和抗体的 mPFC 内输注，以测试 BDNF 释放在驱动东莨菪碱诱导的行为反应中的必要性。进行了进一步的体内和体外实验，以描绘东莨菪碱作用背后的 BDNF 依赖性机制。结果 我们发现 BDNF Met/Met 小鼠对东莨菪碱的反应减弱，并且抗 BDNF 抗体注入 mPFC 阻止了东莨菪碱的抗抑郁样行为效应。体外实验表明东莨菪碱迅速刺激BDNF释放和原肌球蛋白受体激酶B-细胞外信号调节激酶信号传导。此外，这些作用需要 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体激活并被神经元沉默阻断。重要的，用维拉帕米预处理可防止东莨菪碱诱导的行为反应和 BDNF-原肌球蛋白受体激酶 B 信号传导，表明这些作用取决于电压依赖性钙通道的激活。结论 结果确定了活性依赖性 BDNF 释放在东莨菪碱的快速抗抑郁作用中的重要作用。BDNF Met 小鼠的反应减弱表明具有 Met 等位基因的患者可能对东莨菪碱的反应较弱。