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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

基本信息

批准号：
8486831
负责人：
Rebekah Coleman Evans
金额：
$ 1.1万
依托单位：
GEORGE MASON UNIVERSITY
依托单位国家：
美国
项目类别：
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/8486831
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

项目摘要

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.

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。本研究调查了皮质纹状体 LTP 发生时 PKA 必须活跃的部位。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。