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Effectors of presynaptic cAMP dependent potentiation at mossy fiber synapses

苔藓纤维突触突触前 cAMP 依赖性增强的效应器

基本信息

批准号：
10501884
负责人：
Anis Contractor
金额：
$ 63.84万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10501884
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 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 postsynaptic presynaptic social synaptic function way finding

项目摘要

SUMMARY 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 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 yet to be 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 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 optoactivation-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.

总结