The Role of PKA Activity and AKAP anchoring in Striatal Synaptic Plasticity

PKA 活性和 AKAP 锚定在纹状体突触可塑性中的作用

• 批准号: 8123817
• 负责人: Rebekah Coleman Evans
• 金额: $ 2.95万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-24 至 2012-11-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123817
• 关键词: A kinase anchoring protein; AMPA Receptors; Address; Adenylate Cyclase; Area; Binding Sites; Brain; Cells; Cognitive deficits; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diffusion; Disease; Dorsal; Drug Delivery Systems; Electrophysiology (science); Equilibrium; Experimental Designs; Fiber; Frequencies; Habits; Hippocampus (Brain); Knockout Mice; Learning; Location; Long-Term Depression; Long-Term Potentiation; Motor; Mus; Mutation; Neurons; Parkinson Disease; Patch-Clamp Techniques; Pathway interactions; Pharmacology; Phosphodiesterase Inhibitors; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Protein Kinase; Proteins; Protocols documentation; Research; Role; Signal Transduction; Site; Source; Structure; Synapses; Synaptic Potentials; Synaptic plasticity; Testing; Training; Transgenic Mice; Vertebral column; base; cognitive function; experimental analysis; motor deficit; mouse model; novel; patch clamp; phosphatase inhibitor; prevent; research study

DESCRIPTION (provided by applicant): Long term plasticity is essential for the proper function of the striatum. It occurs on a timescale of tens of minutes and putatively underlies habit formation and learning. The delicate balance between long term potentiation and long term depression is important for correct motor and cognitive function and is disrupted in striatal based diseases such as Parkinson's Disease (Calabresi et al., 2007). Many molecules are necessary for long term plasticity, but exactly where they need to be active is not well established. Cyclic AMP dependent protein kinase (PKA) is one such molecule. Long term potentiation (LTP) of striatal synapses requires active PKA, but PKA is not randomly located within a neuron. PKA is localized to specific areas of the neuron by A-kinase anchoring proteins (AKAPs). This study investigates where PKA must be active for cortico- striatal LTP to occur. Using electrophysiology, pharmacology, and transgenic mice, I will test whether PKA needs to be anchored pre- or post-synaptically, and whether it needs to be concentrated close to its phosphorylation targets or close to the source of cAMP. I will also investigate the role of one particular AKAP, AKAP150, which has been implicated in striatal learning tasks, but whose role in cortico-striatal plasticity is unknown (Weisenhaus et al., 2010). An in-depth analysis of PKA anchoring in the striatum is an essential step in understanding the intracellular signaling cascades that underlie striatal plasticity. A complete understanding of these pathways will guide research to novel drug targets that address both the motor and the cognitive deficits of Parkinson's Disease. PUBLIC HEALTH RELEVANCE: The correct balance between the strengthening and weakening of neuronal pathways is essential for proper brain function. A disruption of this balance in the dorsal striatum may be the cause of motor and cognitive deficits associated with Parkinson's Disease. This project will examine specific mechanisms underlying the strengthening of dorsal striatum pathways and will yield information helpful for establishing new drug targets and evaluating current treatments for Parkinson's Disease.

描述（由申请人提供）：长期可塑性对于纹状体的正确功能至关重要。它发生在数十分钟的时间范围内，并且推定的是习惯形成和学习的基础。长期增强和长期抑郁之间的微妙平衡对于正确的运动和认知功能很重要，并且在诸如帕金森氏病（Calabresi et al。，2007）等纹状体疾病中受到破坏。许多分子对于长期可塑性都是必需的，但是确切的位置并不能很好地确定它们。环状AMP依赖性蛋白激酶（PKA）就是这样的分子。纹状体突触的长期增强（LTP）需要活跃的PKA，但PKA并非随机位于神经元内。 PKA通过A-激酶锚定蛋白（AKAP）定位于神经元的特定区域。这项研究调查了PKA必须在何处进行皮质纹状体LTP。使用电生理学，药理学和转基因小鼠，我将测试PKA是否需要在突触后或突触后锚定，以及是否需要将其浓缩到其磷酸化靶标接近还是接近cAMP的来源。我还将调查一种特定的AKAP AKAP150的作用，该作用与纹状体学习任务有关，但其在Cortico-Striatal可塑性中的作用尚不清楚（Weisenhaus等，2010）。对纹状体中的PKA的深入分析是理解纹状体可塑性构成的细胞内信号传导级联反应的重要步骤。对这些途径的完整理解将指导研究对帕金森氏病的运动和认知缺陷的新型药物靶标的研究。 公共卫生相关性：神经元途径的加强和削弱之间的正确平衡对于适当的大脑功能至关重要。背纹状体中这种平衡的破坏可能是与帕金森氏病有关的运动和认知缺陷的原因。该项目将研究增强背纹状体途径的特定机制，并将产生有助于建立新药物目标并评估当前帕金森氏病治疗的信息。