Endocannabinoid Metabolism and Synaptic Function

摘要 这项研究项目的长期目标是了解糖尿病的细胞、分子和表观遗传学机制。 内源性大麻素(ECB)信号可能调节突触和神经认知功能。而欧洲央行 众所周知，系统在调节大脑动态平衡、积累信息方面发挥着重要作用 这表明，欧洲央行系统还参与了几种精神和神经障碍。增强 通过抑制ECB代谢来传递ECB信号已被认为是一种有前途的治疗方法。 预防精神和神经认知疾病。然而，我们对潜在机制的理解 通过慢性抑制ECB在突触活动中的代谢来增强ECB信号仍然是有限的。 通过慢性失活增强内源性大麻素2-花生四烯酰甘油(2-AG)信号 单酰基甘油脂肪酶(MAGL)是大脑中水解2-AG的主要酶，已被证明 产生抗抑郁和抗焦虑样作用，并增强海马突触可塑性以及 学习和记忆。我们最近的研究表明，MAGL的持续失活增加了 树突棘和谷氨酸受体亚单位在海马区的表达。这表明 MAGL抑制2-AG信号增强对突触结构和功能可塑性的调节 决定神经回路的活动和相应的神经认知功能。微RNA(MiRNAs)是 非编码的小RNA，负向调节靶分子的表达和功能。然而，我们有 不知道miRNAs靶分子是否参与维持突触结构的完整性和 功能受ECB信号调节。在拟议的研究中，我们将检验这样一个假设，即监管 MAGL慢性失活的突触活动和认知功能是通过2-AG信号介导的 抑制靶向对调节突触活动重要的分子的miRNA。这项研究 在本申请中提出的建议有望进一步加深我们对潜在机制的理解 ECB信号在突触和神经认知功能调节中的增强，这可能导致未来 研究改善治疗和预防精神和神经疾病的策略。

Summary The long-term goal of this research project is to understand cellular, molecular, and epigenetic mechanisms of endocannabinoid (eCB) signaling that may modulate synaptic and neurocognitive functions. While the eCB system is known to play an important role in regulation of brain homeostasis, accumulated information suggests that the eCB system is also involved in several mental and neurological disorders. Augmentation of eCB signaling by inhibition of eCB metabolism has been proposed as a promising therapy for treatment and prevention of mental and neurocognitive illnesses. However, our understanding of the mechanisms underlying augmentation of eCB signaling by chronic inhibition of eCB metabolism in synaptic activity is still limited. Strengthening endocannabinoid 2-arachidonoylglycerol (2-AG) signaling by chronic inactivation of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes 2-AG in the brain, has been shown to produce antidepressant- and anxiolytic-like effects and enhance hippocampal synaptic plasticity as well as learning and memory. Our recent studies showed that sustained inactivation of MAGL increases the density of dendritic spines and expression of glutamate receptor subunits in the hippocampus. This suggests that augmentation of 2-AG signaling by inhibition of MAGL regulates structural and functional plasticity of synapses that determine activity of neural circuits and corresponding neurocognitive functions. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate expression and function of target molecules. However, we do not know whether miRNAs that target molecules involved in maintaining the integrity of synaptic structure and function are regulated by eCB signaling. In the proposed studies, we will test the hypothesis that regulation of synaptic activity and cognitive function by chronic inactivation of MAGL is through 2-AG signaling-mediated suppression of the miRNA that targets the molecules important for regulation of synaptic activity. The research proposed in this application is expected to further our understanding of the mechanisms underlying augmentation of eCB signaling in regulation of synaptic and neurocognitive functions, which may lead to future research on improving strategies for the treatment and prevention of mental and neurological illnesses.