Role of CaMKII in Structural Synaptic Plasticity

CaMKII 在结构突触可塑性中的作用

• 批准号: 0235519
• 负责人: Gina Turrigiano
• 金额: --
• 依托单位: Brandeis University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2007-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0235519&HistoricalAwards=false
• 关键词: Role; CaMKII; Structural; Synaptic; Plasticity

Circuits of neurons in the mammalian cortex are composed of many thousands of neurons, each of which may receive synaptic contacts from hundreds of other neurons. A central goal of neuroscience is to understand how such complex circuits are wired up correctly during development. It is generally believed that basic cortical circuitry is set up through genetic programming, but that during development this rough connectivity is refined in an activity-dependent manner. Synapses that are effective at driving activity in the postsynaptic neuron are retained, while synapses that are ineffective are lost. Despite the generality of this observation the molecular machinery that allows patterned neuronal activity to "reward" and enhance effective synapses and "punish" ineffective synapses remains unknown. In this project, Dr. Turrigiano's laboratory will test the role of calcium-calmodulin dependent protein kinase II (CaMKII) in such synaptic rewiring of cortical circuits. CaMKII is an attractive candidate to transduce patterned activity into changes in synaptic connectivity because it is activated when synapses effectively drive the postsynaptic neuron, and can have a number of important effects on synaptic transmission. In previous work the PI found that activation of CaMKII has two distinct effects on synaptic connectivity. In the presence of activated CaMKII, synapses that continue to effectively drive the postsynaptic neuron are structurally enhanced, while synapses that do not are eliminated. This suggests that activation of a single molecule can generate an activity-dependent remodeling of synaptic connectivity. In this proposal the PI will combine physiological, molecular, and time-lapse imaging to study the cellular and molecular mechanisms that allow CaMKII to act as either a "punishment" or a "reward" signal for synapse formation. This proposal will foster undergraduate education because Brandeis undergraduates will participate in these experiments in the form of senior honors research projects. In addition the PI has an excellent track record in training women in quantitative scientific methods.

哺乳动物皮层中的神经元回路由数千个神经元组成，每个神经元可以接收来自数百个其他神经元的突触接触。 神经科学的一个中心目标是了解这些复杂的回路在发育过程中是如何正确连接的。人们普遍认为，基本的皮层回路是通过遗传编程建立起来的，但在发育过程中，这种粗略的连接是以活动依赖的方式完善的。有效驱动突触后神经元活动的突触被保留，而无效的突触则丢失。尽管这种观察具有普遍性，但允许模式化神经元活动“奖励”和增强有效突触以及“惩罚”无效突触的分子机制仍然未知。 在这个项目中，Turrigiano博士的实验室将测试钙-钙调蛋白依赖性蛋白激酶II（CaMKII）在皮层回路的突触重新布线中的作用。CaMKII是一个有吸引力的候选者，可以将模式化的活动转化为突触连接的变化，因为当突触有效地驱动突触后神经元时，CaMKII被激活，并且可以对突触传递产生许多重要影响。 在以前的工作中，PI发现CaMKII的激活对突触连接有两种不同的影响。在激活的CaMKII的存在下，继续有效地驱动突触后神经元的突触在结构上得到增强，而不这样做的突触被消除。这表明单个分子的激活可以产生突触连接的活性依赖性重塑。 在这项提议中，PI将结合联合收割机的生理，分子和时间推移成像，研究细胞和分子机制，使CaMKII作为一个“惩罚”或“奖励”信号突触形成。 这项建议将促进本科教育，因为布兰代斯本科生将以高级荣誉研究项目的形式参与这些实验。此外，PI在对妇女进行定量科学方法培训方面有着出色的记录。