Regulation of synaptic plasticity by the cyclic-AMP signalling pathway.

通过环AMP信号通路调节突触可塑性。

• 批准号: RGPIN-2020-04443
• 负责人: Nguyen, Peter
• 金额: $ 2.04万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763301
• 关键词: Regulation; synaptic; plasticity; cyclic; AMP

Learning is the acquisition of new knowledge about the environment, and memory is its retention over time. Much of what we do in the present and future is shaped by what we remember from our past experiences. A major goal of neurobiology is to identify the complex molecular and cellular mechanisms that importantly regulate learning and memory storage in the mammalian brain. Activity-dependent changes in synaptic strength ("synaptic plasticity") are critical for specific forms of learning and memory. Long-term potentiation (LTP) is an activity-induced enhancement of the physiological strength of excitatory synapses widely regarded as a synaptic mechanism for memory. Many of the molecular mechanisms required for LTP to be maintained are also critical for memory function. As such, elucidating the molecular mechanisms that are critical for LTP continues to shed light on the mechanisms of memory storage, and may reveal viable strategies for improving mental health. Numerous signaling pathways have been implicated in both LTP and memory storage in the mammalian hippocampus, a brain structure critical for making new long-term memories. One pathway that is critical for memory storage and synaptic plasticity in a wide range of animal species (from flies and snails to mice) is the cyclic-AMP (cAMP) signaling pathway. This consists mainly of cAMP, cAMP-dependent protein kinase (PKA), and "exchange protein activated by cAMP" (Epac). PKA and Epac are proteins that bind cAMP and are activated by it. PKA is anchored to specific intracellular loci by A-kinase anchoring proteins (AKAPs). Their ability to spatially restrict PKA's effects to specific subcellular compartments of neurons makes them an important determinant of where cAMP signaling can have substantial impact within neurons. Noradrenaline regulates crucial brain functions such as learning, memory, sleep, and attention. Elucidating how noradrenaline impacts synaptic signaling may reveal treatments for memory impairment, PTSD, and other disorders linked to abnormal noradrenergic physiology. My lab has pioneered the identification of PKA, Epac, and AKAPs as key players in modulating LTP following activation of noradrenergic receptors. We will use newly available pharmacological agents that disrupt the functions of specific isoforms of AKAPs and Epac to assess their roles in regulating expression of LTP. These studies will pioneer this area of research by identifying the roles of Epac and AKAPs in synaptic plasticity. Understanding how the brain forms and stores memories is an important milestone that will help elucidate the neural mechanisms of other cognitive processes, such as perception, attention, and "consciousness", that are intimately intertwined with memory processing.

学习是获得有关环境的新知识，记忆是随着时间的推移而保留。我们现在和未来所做的很多事情都是由我们从过去的经历中所记得的东西所塑造的。神经生物学的一个主要目标是确定复杂的分子和细胞机制，重要地调节哺乳动物大脑中的学习和记忆存储。 突触强度的活动依赖性变化（“突触可塑性”）对于特定形式的学习和记忆至关重要。长时程增强（LTP）是一种活动诱导的兴奋性突触生理强度的增强，被广泛认为是记忆的突触机制。许多维持LTP所需的分子机制对记忆功能也至关重要。因此，阐明对LTP至关重要的分子机制将继续阐明记忆储存的机制，并可能揭示改善心理健康的可行策略。 哺乳动物海马体中的LTP和记忆储存都涉及许多信号通路，海马体是一种对形成新的长期记忆至关重要的大脑结构。环磷酸腺苷（cAMP）信号通路是一种对多种动物（从苍蝇、蜗牛到小鼠）的记忆储存和突触可塑性至关重要的通路。它主要由cAMP、cAMP依赖性蛋白激酶（PKA）和“cAMP激活的交换蛋白”（Epac）组成。PKA和Epac是结合cAMP并被其激活的蛋白质，PKA通过A-激酶锚定蛋白（AKAP）锚定到特定的细胞内位点。它们在空间上将PKA的作用限制在神经元的特定亚细胞区室的能力使它们成为cAMP信号传导在神经元内何处具有实质性影响的重要决定因素。去甲肾上腺素调节重要的大脑功能，如学习，记忆，睡眠和注意力。阐明去甲肾上腺素如何影响突触信号可能揭示记忆障碍，创伤后应激障碍和其他与异常去甲肾上腺素能生理学相关的疾病的治疗方法。我的实验室率先识别PKA，Epac和AKAP作为去甲肾上腺素能受体激活后调节LTP的关键参与者。 我们将使用新的药理学试剂，破坏AKAP和Epac的特定亚型的功能，以评估它们在调节LTP表达中的作用。这些研究将通过确定Epac和AKAP在突触可塑性中的作用来开拓这一研究领域。了解大脑如何形成和存储记忆是一个重要的里程碑，将有助于阐明其他认知过程的神经机制，如感知，注意力和“意识”，这些都与记忆处理密切相关。