Dynamics of the Structure-Function Relationship at Single Postsynaptic Densities

描述(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和记忆的分子机制以及突触功能在疾病中的病理的关键。特别是，谷氨酸能突触功能的病理变化在精神分裂症等精神障碍和自闭症等发育障碍中被发现。兴奋性突触通常形成在被称为棘突的小结构上，这些棘突从突触后神经元的树突突起。突触后特化的基本原理是突触后密度(PSD)，这是一个复杂的蛋白质网络，将谷氨酸受体锚定在神经递质释放部位，招募信号转导分子，并连接到跨突触黏附复合体。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的形态动态发生迅速，在几秒到几分钟的时间尺度上，并受到突触活动的急性变化的调节。由于突触前谷氨酸释放部位与突触后受体的精确对齐是突触传递的关键决定因素，PSD的形态变化可能具有重要的功能后果。该建议将活细胞荧光显微镜与电生理学和谷氨酸光解相结合，以测试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。这一建议超越了现有的脊柱形态测量方法，直接成像完整的突触结构。此外，它还测试了由PSD形态动力学驱动的调节突触功能的新机制。从这些实验中获得的知识将扩大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。一系列认知障碍和神经疾病涉及大脑细胞之间的通讯中断。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。这些信息对于寻找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共卫生至关重要。

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.