Induction pathways in hippocampal adaptive synaptic plasticity

海马适应性突触可塑性的诱导途径

• 批准号: 7941000
• 负责人: Devon C Crawford
• 金额: $ 2.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941000
• 关键词: Acute; Adverse effects; Alzheimer' s Disease; Biological; Biological Neural Networks; Brain; Cell Death; Cells; Communication; Confocal Microscopy; Cyclic AMP; DNA; Data; Depressed mood; Environment; Epilepsy; Event; Exhibits; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamates; Goals; Healthcare Systems; Hippocampus (Brain); Huntington Disease; Image; Individual; Injury; Laboratories; Learning; Maintenance; Memory; Modification; Molecular; Neuroglia; Neurons; Neurosciences; Parkinson Disease; Pathway interactions; Pertussis Toxin; Physiology; Presynaptic Terminals; Process; Rattus; Rodent; Role; Seizures; Signal Transduction; Source; Stroke; Synapses; Synaptic plasticity; Techniques; Testing; Training; Transfection; Traumatic Brain Injury; Work; career; extracellular; immunocytochemistry; insight; medical specialties; neuron development; neuroprotection; postsynaptic; presynaptic; research study; skills; synaptic depression

DESCRIPTION (provided by applicant): Every year, millions of people within the U.S. suffer from conditions like epilepsy, stroke, traumatic brain injury, Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease while billions of dollars are spent treating them in our healthcare system. All of these conditions have in common the presence of excitotoxic injury in the brain, which is characterized by increased neuronal activity and cell death. We are studying a form of adaptive synaptic plasticity that may be neuroprotective during such excitatory insults in addition to its role for setting synaptic efficacy during normal activity. In glutamatergic neurons of the hippocampus, the number of functionally active presynaptic terminals is decreased after prolonged periods of increased activity. In addition to neuroprotection, we believe that this activity-dependent plasticity may underlie temporary learning and memory problems that follow acute brain insults due to the subsequently depressed synaptic activity and may also be vital for neuronal development and network maintenance. This proposal aims to elucidate the cellular mechanisms responsible for inducing adaptive presynaptic silencing by utilizing sophisticated imaging, electrophysiological, and molecular biological techniques in primary rat hippocampal culture. The goal of Aim 1 is to determine whether adaptive presynaptic silencing is a cell- autonomous process or whether signals passed between cells are necessary for induction. We will do so by depolarizing individual neurons within a network of non-depolarized cells and by testing the role of postsynaptic neurons and glial cells. This will clarify the source of the signaling cascade responsible for this synaptic phenomenon and will contribute to our currently limited understanding of how neurons adjust to their dynamic extracellular environments. We have preliminary data that implicate inhibitory G-proteins in the induction of adaptive presynaptic silencing, so the goal of Aim 2 is to begin elucidating the upstream and downstream G-protein signaling cascades. We will test whether G-protein-coupled receptors upstream of inhibitory G-proteins modulate silencing and whether cAMP signaling is depressed during prolonged periods of increased activity. This aim identifies potential pharmacological targets to exploit for treatment of excitotoxic injury or its reversible side effects. Overall, this project will elucidate upstream signaling mechanisms governing an underappreciated form of synaptic malleability and will provide training for the applicant in techniques important for a future career in cellular neuroscience.

描述（由申请人提供）：每年，美国有数百万人患有癫痫、中风、创伤性脑损伤、阿尔茨海默病、帕金森病和亨廷顿病等疾病，而我们的医疗保健系统花费了数十亿美元来治疗这些疾病。所有这些病症的共同之处在于脑中存在兴奋性毒性损伤，其特征在于神经元活性增加和细胞死亡。我们正在研究一种适应性突触可塑性的形式，除了在正常活动中设置突触功效的作用外，它在这种兴奋性损伤中可能具有神经保护作用。在海马的海马能神经元中，功能活跃的突触前末梢的数量在长时间的活动增加后减少。除了神经保护之外，我们认为这种活动依赖性可塑性可能是由于随后抑制的突触活动导致急性脑损伤后的暂时学习和记忆问题的基础，并且对于神经元发育和网络维护也可能至关重要。本研究的目的是利用先进的影像学、电生理学和分子生物学技术，在原代培养的大鼠海马中，阐明诱导适应性突触前沉默的细胞机制。目的1的目标是确定适应性突触前沉默是否是一个细胞自主的过程，或者细胞之间传递的信号是否是诱导所必需的。我们将通过去极化非去极化细胞网络中的单个神经元，并通过测试突触后神经元和神经胶质细胞的作用来实现。这将澄清负责这种突触现象的信号级联的来源，并将有助于我们目前有限的了解神经元如何适应其动态的细胞外环境。我们有初步的数据表明抑制性G蛋白参与了适应性突触前沉默的诱导，因此目标2的目标是开始阐明上游和下游G蛋白信号级联。我们将测试抑制性G蛋白上游的G蛋白偶联受体是否调节沉默，以及在长时间的活性增加期间cAMP信号传导是否受到抑制。这一目标确定了潜在的药理学靶点，以利用治疗兴奋性毒性损伤或其可逆的副作用。总的来说，这个项目将阐明上游信号传导机制，控制一种未被充分认识的突触可塑性形式，并将为申请人提供对细胞神经科学未来职业生涯重要的技术培训。