Role of CaMKII in Structural Synaptic Plasticity

点击翻译按钮获取中文摘要

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.