Dynamic Regulation of Neurotransmitter Release

神经递质释放的动态调节

基本信息

批准号：
7220626
负责人：
NICOLE CALAKOS
金额：
$ 16.64万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7220626
关键词：
Acute Address Behavioral Binding Class Cyclic AMP-Dependent Protein Kinases Dementia Disease Dystonia Gene Deletion Gene Transfer Genes Health Hour Information Storage Knock-out Lead Length Mediating Modification Molecular Neurons Phosphorylation Phosphorylation Site Physiology Preparation Process Property Protein Binding Domain Protein Isoforms Protein Overexpression Proteins Range Regulation Role Scaffolding Protein Serine Slice Structure Synapses Synaptic Vesicles Synaptic plasticity Techniques Therapeutic Thinking Viral Work addiction base dentate gyrus drug development experience hippocampal pyramidal neuron in vivo insight millisecond mossy fiber mutant neural circuit neuropsychiatry neurotransmission neurotransmitter release postsynaptic presynaptic rab3A GTP-Binding Protein research study scaffold synaptic function synaptotagmin I therapy development tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Elucidating the molecular basis of synaptic plasticity will lead to a more sophisticated understanding of the neural circuit modifications which underlie experience-dependent plasticity in both health and disease. Much is known about the mechanisms of postsynaptic forms of long lasting plasticity. By comparison, however, relatively little is known about the mechanisms of presynaptic plasticity. This proposal focuses on understanding the synaptic functions of a class of presynaptic, active zone proteins, RIMs, because of their requirement in a prominent form of presynaptic LTP and their additional roles in basal neurotransmitter release and short-term plasticity. RIMs have several protein binding domains that interact with key components of synaptic vesicles and active zones. Because of this, RIMs have been described as presynaptic "scaffold" proteins. As a scaffold, RIM is a powerful tool to gain insight to the coordinate activities of several important presynaptic proteins. A key outstanding question is to understand how RIM integrates the activities of its binding partners to achieve synaptic plasticity. In this proposal, we will perform rescue experiments in the RIM1a knockout background to delineate the functional significance of RIM1a's interactions with other presynaptic proteins. We will also study the functional significance of a key PKA phosphorylation site that is implicated in mediating LTP. Lastly, we will evaluate the functional significance of the RIM2 gene products. Are they functionally redundant or does expression of a particular RIM isoform convey distinct synaptic properties? To perform these experiments we will use electrophysiological recording techniques on both culture and acute slice preparations in combination with molecular techniques to allow gene transfer into the knockout background. A precise understanding of the molecular interactions that underlie presynaptic plasticity as described in this proposal is critical both to enable studies of the behavioral significance of presynaptic plasticity and to enable targeting these proteins for the development of therapies for a wide range of neuropsychiatric diseases that may involve synaptic plasticity such as dementia, dystonia and addiction.

描述（由申请人提供）：阐明突触可塑性的分子基础将导致对神经回路修饰的更复杂的理解，这些修饰是健康和疾病中经验依赖性可塑性的基础。关于持久可塑性的突触后形式的机制知之甚少。但是，相比之下，对突触前可塑性的机制知之甚少。该建议的重点是理解一类突触前的活性区蛋白（RIMS）的突触功能，因为它们以突触前LTP的突出形式需要，及其在基础神经递质释放和短期可变性中的额外作用。边缘具有几个蛋白结合结构域，这些结构域与突触囊泡和活性区域的关键成分相互作用。因此，RIM被描述为突触前的“支架”蛋白。作为脚手架，RIM是一种有力的工具，可以洞悉几种重要的突触前蛋白的坐标活动。一个关键的问题是了解RIM如何整合其结合伙伴的活动以实现突触可塑性。在此提案中，我们将在RIM1A敲除背景中进行救援实验，以描述RIM1A与其他突触前蛋白相互作用的功能意义。我们还将研究与介导LTP有关的关键PKA磷酸化位点的功能意义。最后，我们将评估RIM2基因产物的功能意义。它们在功能上是多余的还是特定边缘同工型的表达传达不同的突触特性？为了执行这些实验，我们将在培养物和急性切片制剂上使用电生理记录技术与分子技术结合使用，以允许基因转移到敲除背景中。对本提案中突触前可塑性构成的分子相互作用的精确理解至关重要，这既是对突触前可塑性的行为意义的研究至关重要突触可塑性，例如痴呆，肌张力障碍和成瘾。