Dynamics of the Structure-Function Relationship at Single Postsynaptic Densities

描述（由申请人提供）：神经元通过形成称为突触的特殊连接在大脑中的网络中传递信息。单个突触的功能是理解学习记忆分子机制和疾病中突触功能病理的关键。特别是，在精神分裂症等精神疾病和自闭症等发育障碍中发现了谷氨酸突触功能的病理改变。兴奋性突触通常形成于突起于突触后神经元树突的小结构棘上。突触后特化的原理是一个突出的突触后密度（PSD），这是一个复杂的蛋白质网络，它将谷氨酸受体锚定在神经递质释放位点之外，招募信号转导分子，并连接到跨突触粘附复合物。我们的实验室最近描述了活神经元中PSD结构支架的协调重排。PSD形态动态发生迅速，在几秒到几分钟的时间尺度上，并由突触活动的急性变化调节。由于突触前谷氨酸释放位点与突触后受体的精确对齐是突触传递的关键决定因素，PSD形态学变化可能具有重要的功能后果。本研究拟将活细胞荧光显微镜与电生理学和谷氨酸光解相结合，检验PSD形态动力学是否调节突触传递和可塑性，以及个体PSD重塑行为是否由突触强度决定。该建议通过直接成像完整的突触结构，扩展了现有的脊柱形态学测量。此外，它还测试了由PSD形态动力学驱动的突触功能调节的新机制。从这些实验中获得的知识将扩展我们对学习和记忆的分子机制的理解，并有助于确定诊断、治疗和减轻精神疾病负担的新策略。许多认知障碍和神经系统疾病都与大脑细胞间的通讯中断有关。这里提出的实验有助于阐明这些细胞如何相互交流的基本机制，以及它们如何通过改变短时间和长时间尺度上的交流强度来存储信息。这些信息对于发现精神障碍的原因和设计新的预防、诊断和治疗战略以改善公众健康至关重要。

DESCRIPTION (provided by applicant): Neurons communicate information across networks in the brain by forming specialized connections called synapses. The function of individual synapses is key to understanding molecular mechanisms of learning and memory and the pathology of synapse function in disease. In particular, pathological changes in the function of glutamatergic synapses are found in psychiatric disorders like schizophrenia and developmental disorders such as autism. Excitatory synapses generally form on small structures called spines, which protrude from the dendrite of the postsynaptic neuron. The principle postsynaptic specialization is a prominent postsynaptic density (PSD), a complex protein network that anchors glutamate receptors across from sites of neurotransmitter release, recruits signal transduction molecules, and connects to trans-synaptic adhesion complexes. Our laboratory has recently described coordinated rearrangement of the PSD structural scaffold in living neurons. PSD morphological dynamics occur rapidly, on a time scale of seconds to minutes, and are regulated by acute changes in synaptic activity. Because precise alignment of presynaptic glutamate release sites with postsynaptic receptors is a critical determinant of synaptic transmission, PSD morphological changes may have important functional consequences. This proposal combines live-cell fluorescent microscopy with electrophysiology and glutamate photolysis to test whether PSD morphological dynamics regulate synaptic transmission and plasticity and whether individual PSD reshaping behavior is set by synapse strength. This proposal extends beyond existing measures of spine morphology by directly imaging an integral synapse structure. Furthermore, it tests new mechanisms for regulating synaptic function driven by PSD morphological dynamics. Knowledge gained from these experiments will extend our understanding of the molecular mechanisms of learning and memory and help to define new strategies for diagnosing, treating, and ameliorating the burden of mental illnesses. A broad range of cognitive disorders and neurological diseases involve a disruption of communication between cells in the brain. The experiments proposed here help illuminate fundamental mechanisms of how these cells communicate with one another, and how they store information through altering the strength of communication over both short and long time scales. Such information will be essential to finding the cause of mental disorders and to designing new prevention, diagnosis, and treatment strategies to improve public health.