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常功能至关重要。它发生的时间尺度为数十分钟，并且被认为是习惯形成和学习的基础。长期增强和长期抑制之间的微妙平衡对于正确的运动和认知功能非常重要，并且在帕金森病等纹状体疾病中被破坏（Calabresi 等，2007）。许多分子对于长期可塑性是必需的，但它们需要在何处发挥作用尚不清楚。环AMP依赖性蛋白激酶(PKA)就是这样的一种分子。纹状体突触的长时程增强 (LTP) 需要活跃的 PKA，但 PKA 并不是随机位于神经元内。 PKA 通过 A 激酶锚定蛋白 (AKAP) 定位于神经元的特定区域。本研究调查了 PKA 必须在何处活跃才能发生皮质纹状体 LTP。我将利用电生理学、药理学和转基因小鼠来测试 PKA 是否需要锚定在突触前或突触后，以及是否需要集中在靠近其磷酸化靶标或靠近 cAMP 来源的位置。我还将研究一种特定的 AKAP AKAP150 的作用，它与纹状体学习任务有关，但其在皮质纹状体可塑性中的作用尚不清楚（Weisenhaus 等人，2010）。深入分析纹状体中的 PKA 锚定是了解纹状体可塑性背后的细胞内信号级联的重要一步。对这些途径的全面了解将指导研究新的药物靶点，以解决帕金森病的运动和认知缺陷。 公共健康相关性：神经元通路的增强和减弱之间的正确平衡对于大脑的正常功能至关重要。背侧纹状体这种平衡的破坏可能是帕金森病相关运动和认知缺陷的原因。该项目将研究加强背侧纹状体通路的具体机制，并将产生有助于建立新药物靶点和评估帕金森病现有治疗方法的信息。