CRCNS: Spatial & Temporal Aspects of cAMP/PKA Signaling Underlying Information

CRCNS：空间

• 批准号: 7900516
• 负责人: EDWIN TED G. ABEL
• 金额: $ 36.01万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900516
• 关键词: A kinase anchoring protein; Affect; Alcohol consumption; Alcoholic Intoxication; Alcoholism; Alcohols; Alzheimer' s Disease; Biochemical; Biochemistry; Brain; Calcium Channel; Cognitive deficits; Computer Simulation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dopamine; Dopamine D1 Receptor; Electrophysiology (science); Ethanol; Experimental Models; Fetal Alcohol Exposure; Hippocampus (Brain); Image; Information Storage; Ion Channel; Learning; Long-Term Potentiation; Measures; Mediating; Memory; Mental Depression; Mental disorders; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurologic; Neurons; Pathway interactions; Pattern; Phase; Play; Potassium Channel; Principal Investigator; Prosencephalon; Protein Kinase; Protein Kinase Inhibitors; Protein phosphatase; Proteins; Receptor Signaling; Research; Role; Schizophrenia; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Slice; Source; Specificity; Stimulus; Structure; Synapses; Synaptic plasticity; Testing; Training; Yang; base; clinically relevant; conditioning; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; innovation; insight; neural circuit; novel; phosphoric diester hydrolase; protein complex; protein kinase A kinase; protein kinase inhibitor; receptor; research study; sedative; synaptic function

DESCRIPTION (provided by applicant): The ability of neurons within the hippocampus to differentially respond to specific temporal and spatial patterns of stimulation underlies the storage of memory and information in neural circuits. Signal transduction pathways are critical for information storage, and alterations in key signaling molecules, such as the cAMP-dependent protein kinase (PKA) signaling pathway, modify both hippocampus-dependent learning and a form of synaptic plasticity known as long-term potentiation (L-LTP). Alterations in these signaling pathways play a critical role in neurological and psychiatric disorders such as alcoholism, depression, schizophrenia and Alzheimer's disease. Despite this clinical relevance, little is known about how signaling pathways respond differentially to distinct temporal and spatial patterns of synaptic input. The dynamics of PKA localization to subcellular compartments by A-Kinase Anchoring Proteins (AKAPs) provides a potential mechanism for such spatial and temporal specificity. We propose an innovative and transformative set of experiments to investigate the critical role of multi-protein complexes involving PKA and AKAPs in neuronal information storage and synaptic plasticity. SPECIFIC AIM 1. Define the role of protein kinase A (PKA) in the temporal sensitivity of late phase long-term potentiation (L-LTP). Fluorescent imaging, electrophysiology, biochemistry and computational modeling will be utilized to measure the level of cAMP and PKA activity after LTP inducing stimuli. These integrated experiments and modeling will evaluate the role of NMDA and D1 receptor signaling in long-lasting forms of synaptic plasticity, and will evaluate the temporal sensitivity of interactions between signaling pathways activated by these receptors. SPECIFIC AIM 2. Define the spatial specificity of biochemical signaling mechanisms underlying L-LTP induction in hippocampal neurons. Computational modeling, fluorescent imaging and electrophysiology approaches will be utilized to measure L-LTP and gradients of cAMP and PKA activity in the presence or absence of inhibitors of PKA anchoring. Successful completion of the research will form the basis for investigating how alterations in this pathway contributes to psychiatric disease such as schizophrenia and alcoholism.

描述(由申请人提供)：海马体内神经元对刺激的特定时间和空间模式做出不同反应的能力是在神经回路中存储记忆和信息的基础。信号转导通路对信息存储至关重要，而关键信号分子的改变，如cAMP依赖的蛋白激酶信号通路，既改变了海马依赖的学习，也改变了一种被称为长时程增强的突触可塑性(L-LTP)。这些信号通路的改变在酒精中毒、抑郁症、精神分裂症和阿尔茨海默病等神经和精神疾病中起着关键作用。尽管有这种临床相关性，但对于信号通路如何对突触输入的不同时间和空间模式做出不同的反应，人们知之甚少。A-Kinase锚定蛋白(AKAPs)将PKA定位到亚细胞室的动态变化为这种时空特异性提供了潜在的机制。我们提出了一套创新和变革性的实验来研究涉及PKA和AKAP的多蛋白复合体在神经元信息存储和突触可塑性中的关键作用。目的1.明确蛋白激酶A(PKA)在晚期长时程增强(LTP)时间敏感性中的作用。荧光成像、电生理学、生物化学和计算模型将被用来测量LTP诱导刺激后cAMP水平和PKA活性。这些综合的实验和模型将评估NMDA和D1受体信号在突触长期可塑性中的作用，并将评估由这些受体激活的信号通路之间相互作用的时间敏感性。目的2.明确L-LTP诱导的海马神经元生化信号机制的空间特异性。计算模型、荧光成像和电生理学方法将被用来测量在存在或不存在PKA锚定抑制剂的情况下，L-LTP以及cAMP和PKA活性的梯度。这项研究的成功完成将为研究这一途径的变化如何导致精神分裂症和酗酒等精神疾病奠定基础。