Aggregation of presynaptic proteins during LTP

LTP 期间突触前蛋白的聚集

• 批准号: 6989047
• 负责人: ROBERT D HAWKINS
• 金额: $ 18.43万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989047
• 关键词: Aggregation; presynaptic; proteins; during; LTP

DESCRIPTION (provided by applicant): Long-lasting potentiation at hippocampal synapses is a form of synaptic plasticity that is thought to be a likely substrate of mammalian learning and memory. To investigate mechanisms of the potentiation, we recently examined immunoreactivity for pre- and postsynaptic proteins during potentiation in dissociated cultures of hippocampal neurons (Antonova et al., 2001). Consistent with recent studies, we found that there is an increase in clusters (puncta) of postsynaptic proteins (GluR1, PSD95) at the onset of long-lasting potentiation. However, we also found that these postsynaptic changes are accompanied by a rapid increase in clusters of presynaptic proteins (synaptophysin, synapsin I, synuclein) and sites where the pre- and postsynaptic proteins colocalize and therefore might participate in functional synapses. We now propose to extend these findings in two ways. First, we will examine the significance of the new presynaptic puncta by testing whether they participate in new functional synapses immediately, or whether they are part of structures that mature into functional synapses with the passage of time. Because the assembly of colocalized pre- and postsynaptic puncta is reminiscent of early synaptogenesis and the later stages of potentiation are accompanied by the growth of new synapses, it is attractive to think that the new puncta might represent a step in that process. We therefore propose to investigate whether long-lasting potentiation involves the coordinated assembly of a variety of synaptic components, as occurs during synaptic development. Second, we will begin to investigate retrograde messengers that may be involved in the formation of the new puncta, including freely diffusible molecules such as NO, extracellular messengers such as neurotrophins, and adhesion molecules. We will also investigate possible presynaptic effectors of these messengers, focusing on ones that are known to be involved in regulating the actin cytoskeleton, which plays a critical role in the increase in presynaptic puncta. These studies should provide new information about the functional significance and molecular mechanisms of a novel aspect of synaptic plasticity that may be important for learning and memory.

描述(申请人提供)：海马区突触的长时间增强是突触可塑性的一种形式，被认为是哺乳动物学习和记忆的可能底物。为了研究这种增强的机制，我们最近在分离的海马神经元培养中检测了突触前和突触后蛋白在增强过程中的免疫反应性(Antonova等人，2001年)。与最近的研究一致，我们发现在长时间增强开始时，突触后蛋白(GluR1，PSD95)的簇(斑点)增加。然而，我们也发现，这些突触后的变化伴随着突触前蛋白簇(突触素、突触素I、突触核蛋白)的迅速增加，以及突触前蛋白和突触后蛋白共同定位的位置，因此可能参与功能性突触。我们现在建议从两个方面扩展这些发现。首先，我们将通过测试它们是否立即参与新的功能性突触，或者它们是否是随着时间的推移成熟为功能性突触的结构的一部分来检验新的突触前点状结构的意义。由于共同定位的突触前和突触后点状突触的组装使人想起早期的突触发生，而增强的后期伴随着新突触的生长，因此人们很有兴趣认为新的突触点状结构可能代表着这一过程中的一步。因此，我们建议研究长时间增强是否涉及各种突触组件的协调组装，就像突触发育过程中发生的那样。其次，我们将开始研究可能参与新斑点形成的逆行信使，包括可自由扩散的分子，如NO，细胞外信使，如神经营养因子，以及黏附分子。我们还将研究这些信使可能的突触前效应器，重点是那些已知参与调节肌动蛋白细胞骨架的信使，肌动蛋白细胞骨架在突触前点数的增加中起着关键作用。这些研究应该为突触可塑性的一个可能对学习和记忆重要的新方面的功能意义和分子机制提供新的信息。