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Synaptic transport of endocannabinoids in the brain

大脑中内源性大麻素的突触转运

基本信息

批准号：
10576852
负责人：
SAMIR HAJ-DAHMANE
金额：
$ 53.13万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576852
关键词：
2-arachidonylglycerol Address Anabolism Anxiety Area Astrocytes Behavioral Biochemical Biology Brain Brain region CNR1 gene Carrier Proteins Cells Cytosol Development Diffusion Disease Electrophysiology (science)Endocannabinoids Engineering Enzymes Excitatory Synapse FABP5 gene Family Functional disorder Future Genetic Glutamates Hippocampus Hydrophobicity Inhibitory Synapse Knockout Mice Lipids LoxP-flanked allele Mediating Mental Depression Mental disorders Mus Nature Neurons Outcome Study Output Pathologic Physiological Play Population Positioning Attribute Presynaptic Terminals Process Proteins Psychiatric therapeutic procedure Receptor Activation Reporting Role Signal Transduction Signaling Molecule Solubility Synapses Synaptic Cleft Synaptic Transmission Synaptic plasticity Testing Variant Ventral Tegmental Area Viral aqueous autism spectrum disorder brain dysfunction cannabinoid receptor cognitive reappraisal dorsal raphe nucleus emotion regulation endocannabinoid signaling endogenous cannabinoid system fatty acid-binding proteins gamma-Aminobutyric Acid genetic approach improved lipid transport lipophilicity nervous system disorder neurotransmission neurotransmitter release new therapeutic target novel novel therapeutic intervention pharmacologic postsynaptic neurons presynaptic synaptic function therapeutic target therapy development

项目摘要

Project Summary The endocannabinoid (eCB) system plays a key role in regulating synaptic function in the brain. Dysfunction of eCB signaling contributes to numerous psychiatric and neurological disorders including anxiety, depression, and autism. Consequently, the development of treatments for disorders involving eCB dysfunction requires a thorough understanding of the mechanisms regulating eCB signaling in the brain. It is well-established that physiological and/or pathological activation of postsynaptic neurons leads to the biosynthesis and release of the eCB 2-arachidonoylglycerol (2-AG). Once released, 2-AG traverses the synaptic cleft and activates cannabinoid receptors located on presynaptic axon terminals, which mediate its behavioral and physiological effects. Although considerable progress has been made in elucidating how 2-AG signaling controls synaptic function and behavioral outputs, the mechanism(s) governing synaptic 2-AG transport remains unknown, highlighting a major gap in our fundamental understanding of 2-AG signaling in the brain. The lipophilic nature of 2-AG limits its diffusion across the synapse, suggesting the existence of a carrier(s) that facilitates 2-AG transport to permit cannabinoid receptor activation. Identification of a synaptic 2-AG carrier would not only greatly enhance our basic understanding of 2-AG signaling but could also lead to the discovery of a new therapeutic target(s) to treat disorders involving eCB dysfunction. To that end, our group has recently identified fatty acid binding proteins (FABPs) as intracellular carriers for eCBs. In this application, we will build upon this progress and test the novel hypothesis that FABP5, secreted by astrocytes, functions as a synaptic carrier that is essential for 2-AG signaling in multiple brain areas. In Aim 1, we will employ complementary pharmacological and genetic approaches to test the hypothesis that FABP5 mediates retrograde 2-AG transport at inhibitory and excitatory synapses in the hippocampus and ventral tegmental area, brain areas involved in cognitive and emotional regulation. In Aim 2, we will employ our novel FABP5Flox/Flox mice to delineate the roles of astrocytic and neuronal FABP5 in controlling synaptic 2-AG transport. Aim 3 will characterize the contributions of intracellular and secreted FABP5 in mediating 2-AG transport at hippocampal and ventral tegmental area synapses. Successful completion of this proposal will position FABP5 as a synaptic carrier for 2-AG at central synapses, which will greatly enhance our basic understanding of eCB signaling and may facilitate the development of future therapeutics targeting disorders involving eCB dysfunction.

项目总结