Role of CaMKII in Structural Synaptic Plasticity

哺乳动物皮层的神经元回路由成千上万个神经元组成，每个神经元都可能接受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在发育过程中这些复杂的回路是如何正确连接起来的。人们普遍认为，基本的皮质回路是通过遗传程序建立起来的，但在发育过程中，这种粗略的连接以一种依赖于活动的方式被完善。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。尽管这一观察结果具有普遍性，但允许有模式的神经元活动“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-钙调素依赖性蛋白激酶II （CaMKII）在皮层回路突触重新布线中的作用。CaMKII是将模式活动转化为突触连通性变化的一个有吸引力的候选者，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。在之前的研究中，PI发现CaMKII的激活对突触连接有两种不同的影响。在活化CaMKII存在的情况下，继续有效驱动突触后神经元的突触在结构上得到增强，而不这样做的突触则被消除。这表明单个分子的激活可以产生突触连通性的活动依赖性重塑。在这个提议中，PI将结合生理、分子和延时成像来研究细胞和分子机制，使CaMKII作为突触形成的“惩罚”或“奖励”信号。这项提案将促进本科教育，因为布兰代斯的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在培训妇女使用定量科学方法方面有着良好的记录。

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.