Changing Roles of Protein Kinases: Synaptic Plasticity

蛋白激酶作用的变化：突触可塑性

• 批准号: 6928547
• 负责人: MARC KLEIN
• 金额: $ 21.95万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928547
• 关键词: Aplysia; age difference; behavioral /social science research tag; behavioral habituation /sensitization; conditioning; enzyme activity; memory; molecular psychobiology; neural plasticity; neural transmission; protein kinase A; protein kinase C; synapses

DESCRIPTION (provided by applicant): Early stages of memory formation involve the activation of biochemical pathways that modulate neuronal communication. In particular, protein kinases play key roles in the synaptic changes that underlie forms of learning as diverse as short-term behavioral sensitization in invertebrates and long-lasting fear conditioning in mammals. As these roles become progressively clearer, it is becoming apparent that the contribution of different kinases is not fixed, but can vary as a result of prior experience and maturational stage. Modulation of transmission at the sensory neuron-motor neuron synapses of Aplysia contributes importantly to the changes induced by training in the defensive withdrawal reflex. Synaptic transmission is modulated by activity in the sensory neurons and by modulatory neurotransmitters. Synaptic facilitation, associated with behavioral sensitization, is caused by activation of protein kinases in the sensory neurons. At unstimulated synapses, facilitation is mediated primarily by protein kinase A (PKA), while facilitation that follows extensive stimulation is mediated mainly by protein kinase C (PKC). A similar change in the relative contributions of PKA and PKC to facilitation occurs as the animal matures. In addition, facilitation at synapses from mature animals varies with initial synaptic strength. The goals of this project are: 1) To define the physiological targets of the kinases contributing to plasticity: Which aspects of synaptic transmission are modulated by each kinase? 2) To characterize the change in the contributions of the kinases with stimulation: Are the kinases activated differently? Do their targets change? Does the sensitivity of the targets to the kinases change? 3) To determine whether there are synapse-specific differences in kinase involvement that resemble those between synapses of mature and immature animals: Does the variation in facilitation with synaptic strength result from differential contributions of the kinases or from a switch in their targets? Understanding the biological processes that underlie learning and memory would have implications for the treatment of disorders of memory, such as those that accompany Alzheimer's disease. Understanding how background factors such as prior experience and stage of maturation influence the formation of new memories could suggest how therapeutic strategies would need to be tailored to address the particular processes involved in memory formation in different behavioral and developmental states.

描述（由申请人提供）：记忆形成的早期阶段涉及调节神经元通讯的生化途径的激活。特别是，蛋白激酶在突触变化中发挥着关键作用，突触变化是多种学习形式的基础，例如无脊椎动物的短期行为敏化和哺乳动物的长期恐惧调节。随着这些作用逐渐变得更加清晰，越来越明显的是，不同激酶的贡献不是固定的，而是可能因先前的经验和成熟阶段而变化。海兔感觉神经元-运动神经元突触的传递调节对于防御性撤退反射训练引起的变化起着重要作用。突触传递由感觉神经元的活动和调节性神经递质调节。与行为敏化相关的突触促进是由感觉神经元中蛋白激酶的激活引起的。在未刺激的突触中，促进作用主要由蛋白激酶 A (PKA) 介导，而广泛刺激后的促进作用主要由蛋白激酶 C (PKC) 介导。随着动物的成熟，PKA 和 PKC 对促进的相对贡献也会发生类似的变化。此外，成熟动物突触的促进作用随初始突触强度的变化而变化。该项目的目标是： 1) 定义有助于可塑性的激酶的生理目标：每种激酶调节突触传递的哪些方面？ 2) 表征激酶随刺激的贡献变化：激酶的激活方式是否不同？他们的目标有变化吗？靶标对激酶的敏感性是否发生变化？ 3) 确定激酶参与中是否存在突触特异性差异，类似于成熟和未成熟动物突触之间的差异：突触强度促进的变化是由激酶的不同贡献还是由其靶标的转换引起的？了解学习和记忆背后的生物过程将对治疗记忆障碍（例如伴随阿尔茨海默病的记忆障碍）产生影响。了解先前经历和成熟阶段等背景因素如何影响新记忆的形成，可以表明需要如何调整治疗策略来解决不同行为和发育状态下记忆形成所涉及的特定过程。