Mechanisms of cAMP dependent potentiation of mossy fiber synapses

苔藓纤维突触 cAMP 依赖性增强机制

基本信息

批准号：
10201932
负责人：
Anis Contractor
金额：
$ 55.3万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201932
关键词：
Affect Aging Alzheimer&apos s Disease Anatomy Animals Anxiety Disorders Behavioral Biochemical Brain Chemosensitization Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dense Core Vesicle Electrophysiology (science)Environment Episodic memory Event Exocytosis Goals Heart Hippocampus (Brain)Impairment In Situ In Vitro Knock-out Label Learning Mammals Mediating Memory Memory impairment Microscopy Molecular Mus Neurodegenerative Disorders Neurons Neuropeptides Pathway interactions Pattern Pharmacology Phosphorylation Physiological Physiology Play Process Proteins Proteomics Research Resolution Retrieval Role Schizophrenia Signal Pathway Signal Transduction Structure Synapses Synaptic Transmission Synaptic Vesicles Synaptic plasticity Testing Vesicle Visit dentate gyrus experience hippocampal pyramidal neuron insight memory process memory retrieval mossy fiber nanoenvironment nervous system disorder neural circuit neuropsychiatric disorder neurotransmitter release optogenetics postsynaptic presynaptic social synaptic function way finding

项目摘要

Synaptic plasticity in the hippocampus is critical to the formation, storage and retrieval of episodic memories. The separate regions of the hippocampus have evolved to play distinct roles in spatial navigation, contextual memories, social memories, and our ability to separate patterns or complete patterns to reconstruct partial memories. In particular the dentate and CA3 regions of the hippocampus are involved in our pattern separation that is vital to the integrity of episodic memories. At the center of this region are the mossy fiber afferents that make conditional detonator synapses onto CA3 pyramidal neurons, which have a distinct form of presynaptic cAMP dependent plasticity. Despite the importance of cAMP plasticity to memory formation and retrieval in the CA3 the exact molecular mechanisms underlying MF LTP have not been uncovered. The premise of this research builds upon our finding that there are at least two downstream cAMP effectors, PKA (protein kinase A) and Epac2 (exchange protein directly activated by cAMP 2), that contribute to cAMP dependent MF LTP. Despite these findings it is still not known how signaling by each of these effectors results in elevated release from MF synapses and, what are the important targets and substrates that are involved in MF LTP. Here we will use a comprehensive approach with leading edge proteomic, biochemical and electrophysiological approaches to determine the signaling partners of the cAMP effectors, and uncover the physiological mechanism of their actions. Thus, in Aim 1 we will take orthogonal approaches to find the interactors and substrates of PKA and Epac2 and validate and verify these by performing high resolution labeling in situ. In Aim 2 we will determine the exact physiological mechanism that underlie increases in release of neurotransmitter at MF synapses using a combined optogenetic-knockout/pharmacological strategy. In the final Aim we will answer the question of how these different but convergent mechanisms are engaged during naturalistic activity patterns, and whether selective disruption of these effectors impairs the ability of mice to separate similar patterns that underlie the formation and retrieval of episodic memories.

海马中的突触可塑性对于情节记忆的形成，存储和检索至关重要。海马的单独区域已经演变为在空间导航中起着不同的作用回忆，社会记忆以及我们分离模式或完整模式以重建部分的能力回忆。特别是海马的齿状区域和CA3区域参与我们的模式分离这对于情节记忆的完整性至关重要。该地区的中心是苔藓纤维传入使有条件的雷管突触到CA3锥体神经元上，该神经元具有独特的突触前形式营地依赖性可塑性。尽管营地可塑性对记忆形成和检索至关重要 CA3尚未发现MF LTP的确切分子机制。这个前提研究基于我们的发现，即至少有两个下游营地效应子PKA（蛋白激酶 A）和EPAC2（由CAMP 2直接激活的交换蛋白），这有助于CAMP依赖的MF LTP。尽管这些发现仍然不知道这些效应子如何导致释放升高来自MF突触，以及MF LTP中涉及的重要目标和底物。在这里，我们将采用一种全面的方法，用于领先的蛋白质组学，生化和电生理方法来确定营地效应子的信号伴侣，并发现其行为的生理机制。因此，在目标1中，我们将采取正交方法找到 PKA和EPAC2的相互作用者和底物并通过执行高分辨率来验证并验证它们原位标记。在AIM 2中，我们将确定基于增加的确切生理机制使用合并的光遗传敲除/药理学策略在MF突触中释放神经递质。在最终目标中，我们将回答这些不同但收敛机制的问题在自然主义活动模式中，以及这些效应子的选择性破坏是否会损害小鼠分开类似的模式，这些模式是情节记忆的形成和检索的基础。