Endocannabinoid Metabolism and Synaptic Function

总结 该研究项目的长期目标是了解细胞，分子和表观遗传机制， 内源性大麻素（eCB）信号传导，其可以调节突触和神经认知功能。尽管欧洲央行 已知系统在调节脑内稳态、积累信息 表明eCB系统也参与了几种精神和神经系统疾病。增强 通过抑制eCB代谢的eCB信号传导已被提出作为治疗和治疗癌症的有前景的疗法。 预防精神和神经认知疾病。然而，我们对潜在机制的理解 通过慢性抑制突触活性中的eCB代谢来增强eCB信号传导仍然是有限的。 通过慢性失活增强内源性大麻素2-花生四烯酰甘油（2-AG）信号传导 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，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 树突棘和海马谷氨酸受体亚单位的表达。这表明 通过抑制MAGL增强2-AG信号传导调节突触的结构和功能可塑性 决定神经回路的活动和相应的神经认知功能。microRNAs（miRNAs） 负调节靶分子表达和功能的小的非编码RNA。但我们 目前还不清楚是否有针对性的miRNA分子参与维持突触结构的完整性， 功能由eCB信号调节。在拟议的研究中，我们将测试这一假设，即调节 MAGL慢性失活引起的突触活动和认知功能是通过2-AG信号转导介导的 抑制靶向调节突触活性的重要分子的miRNA。研究 本申请中提出的方法有望进一步加深我们对潜在机制的理解。 增强eCB信号在调节突触和神经认知功能，这可能导致未来 研究改进治疗和预防精神和神经疾病的战略。

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.