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

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

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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SAMIR HAJ-DAHMANE其他文献

SAMIR HAJ-DAHMANE的其他文献

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{{ truncateString('SAMIR HAJ-DAHMANE', 18)}}的其他基金

Synaptic transport of endocannabinoids in the brain
大脑中内源性大麻素的突触转运
  • 批准号:
    10377918
  • 财政年份:
    2021
  • 资助金额:
    $ 53.13万
  • 项目类别:
Synaptic transport of endocannabinoids in the brain
大脑中内源性大麻素的突触转运
  • 批准号:
    10115932
  • 财政年份:
    2021
  • 资助金额:
    $ 53.13万
  • 项目类别:
Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons
产前乙醇暴露和血清素神经元中的一氧化氮信号传导
  • 批准号:
    10470171
  • 财政年份:
    2018
  • 资助金额:
    $ 53.13万
  • 项目类别:
Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons
产前乙醇暴露和血清素神经元中的一氧化氮信号传导
  • 批准号:
    10228666
  • 财政年份:
    2018
  • 资助金额:
    $ 53.13万
  • 项目类别:
Stress and Endocannabinoids in Serotonin Neurons
血清素神经元中的压力和内源性大麻素
  • 批准号:
    7259555
  • 财政年份:
    2007
  • 资助金额:
    $ 53.13万
  • 项目类别:
Stress and Endocannabinoids in Serotonin Neurons
血清素神经元中的压力和内源性大麻素
  • 批准号:
    7817101
  • 财政年份:
    2007
  • 资助金额:
    $ 53.13万
  • 项目类别:
Stress and Endocannabinoids in Serotonin Neurons
血清素神经元中的压力和内源性大麻素
  • 批准号:
    7619441
  • 财政年份:
    2007
  • 资助金额:
    $ 53.13万
  • 项目类别:
Stress and Endocannabinoids in Serotonin Neurons
血清素神经元中的压力和内源性大麻素
  • 批准号:
    8055456
  • 财政年份:
    2007
  • 资助金额:
    $ 53.13万
  • 项目类别:
Dopamine Mechanisms and Receptors in Raphe 5-HT Neurons
Raphe 5-HT 神经元中的多巴胺机制和受体
  • 批准号:
    6691706
  • 财政年份:
    2001
  • 资助金额:
    $ 53.13万
  • 项目类别:
Dopamine Mechanisms and Receptors in Raphe 5-HT Neurons
Raphe 5-HT 神经元中的多巴胺机制和受体
  • 批准号:
    6621239
  • 财政年份:
    2001
  • 资助金额:
    $ 53.13万
  • 项目类别:

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