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

学习是获得关于环境的新知识，记忆是随着时间的推移而保持的。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记住的东西决定的。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，这些机制对哺乳动物大脑中的学习和记忆存储具有重要的调节作用。 依赖活动的突触强度变化(“突触可塑性”)对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，被广泛认为是一种突触记忆机制。维持LTP所需的许多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存储的机制，并可能揭示改善心理健康的可行策略。 许多信号通路都与哺乳动物海马体的LTP和记忆存储有关，海马体是制造新的长期记忆的关键大脑结构。在许多动物物种(从苍蝇、蜗牛到老鼠)中，对记忆存储和突触可塑性至关重要的一个途径是环磷酸腺苷(CAMP)信号通路。这主要由cAMP、cAMP依赖的蛋白激酶(PKA)和由cAMP激活的交换蛋白(EPAC)组成。PKA和EPAC是结合cAMP并被cAMP激活的蛋白质。PKA通过A-激酶锚定蛋白(AKAPs)锚定于特定的细胞内位点。它们能够在空间上将PKA的作用限制在神经元的特定亚细胞隔间，使它们成为cAMP信号在神经元中的哪个部位产生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。阐明去甲肾上腺素是如何影响突触信号的，可能会揭示记忆障碍、创伤后应激障碍和其他与去甲肾上腺素能生理异常有关的疾病的治疗方法。我的实验室率先确定了PKA、EPAC和AKAP是在去甲肾上腺素受体激活后调节LTP的关键角色。 我们将使用新近可用的药理学药物来破坏特定的AKAPs和EPAC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，开创这一研究领域的先河。 了解大脑是如何形成和存储记忆的是一个重要的里程碑，它将有助于阐明与记忆处理密切相关的其他认知过程的神经机制，如感知、注意和“意识”。

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.