Regulation of synaptic plasticity by BDNF-endocannabinoid interactions

BDNF-内源性大麻素相互作用对突触可塑性的调节

• 批准号: 10307088
• 负责人: Eric S Levine
• 金额: $ 54.11万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307088
• 关键词: 2-arachidonylglycerol; Acute; Affect; Anxiety; Area; Brain; Brain-Derived Neurotrophic Factor; CNR1 gene; Calcium; Cell Line; Coupled; Data; Development; Disease; Electrophysiology (science); Endocannabinoids; Engineering; Epilepsy; Equilibrium; Excitatory Synapse; Exhibits; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Human; Image; Impairment; Individual; Induced pluripotent stem cell derived neurons; Inhibitory Synapse; Instruction; Knowledge; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Mental Depression; Mental disorders; Metabolism; Molecular; Monitor; Motor; Multiple Sclerosis; Mus; Neocortex; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Perception; Pharmacology; Phenotype; Physiological Processes; Play; Population; Prefrontal Cortex; Prosencephalon; Pyramidal Cells; Regulation; Role; Schizophrenia; Sensory; Signal Transduction; Single Nucleotide Polymorphism; Slice; Somatosensory Cortex; Synapses; Synaptic Potentials; Synaptic plasticity; System; anandamide; autism spectrum disorder; cognitive ability; endocannabinoid signaling; experimental study; gamma-Aminobutyric Acid; genetic approach; immunocytochemistry; induced pluripotent stem cell; insight; nervous system disorder; neuroregulation; neurotrophic factor; novel therapeutic intervention; novel therapeutics; painful neuropathy; patch clamp; postsynaptic; presynaptic; release factor; translational impact; translational potential

PROJECT SUMMARY The goal of this project is to explore the functional relevance of interactions between brain-derived neurotrophic factor (BDNF) and endogenous cannabinoids (eCB) in regulating activity-dependent synaptic plasticity in the neocortex and hippocampus. Although there is growing evidence for crosstalk between BDNF and eCBs, little is known regarding potential synaptic interactions. We have previously characterized the synaptic effects of eCBs and BDNF in layer 2/3 and layer 5 of somatosensory cortex as well as the CA1 area of hippocampus, and we have recently shown that the presynaptic effects of BDNF at cortical and hippocampal inhibitory synapses are mediated by the BDNF-induced release of eCBs from postsynaptic pyramidal cells. We have also found that BDNF causes release of eCBs at excitatory synapses, and this eCB signaling mitigates the direct facilitatory effects of BDNF at these synapses. We are now poised to explore the functional relevance of these interactions in regulating activity-dependent synaptic plasticity. In particular, we will examine the interactions between endogenous BDNF-induced eCB release and activity-dependent eCB release in regulating the magnitude and direction of plasticity at excitatory and inhibitory synapses. These studies will combine electrophysiology and calcium imaging with pharmacological and genetic approaches to manipulate these signaling systems. We will also examine these signaling interactions using mice engineered to express common human single-nucleotide polymorphisms (SNPs) that affect either endogenous BDNF or anandamide levels. Importantly, we will carry out parallel studies using cultured human induced pluripotent stem cell (iPSC)-derived neurons generated from individuals who carry these same SNPs.

项目概要 该项目的目标是探索脑源性神经营养细胞之间相互作用的功能相关性 因子（BDNF）和内源性大麻素（eCB）在调节活动依赖性突触可塑性中 新皮质和海马体。尽管越来越多的证据表明 BDNF 和 eCB 之间存在串扰，但很少有证据表明 已知潜在的突触相互作用。我们之前已经描述了 eCB 的突触效应 和 BDNF 位于体感皮层第 2/3 层和第 5 层以及海马 CA1 区，我们 最近表明 BDNF 对皮质和海马抑制性突触的突触前作用是 由 BDNF 诱导的突触后锥体细胞释放 eCB 介导。我们还发现 BDNF 导致兴奋性突触释放 eCB，并且这种 eCB 信号传导减轻了直接促进作用 BDNF 对这些突触的影响。我们现在准备探索这些相互作用的功能相关性 调节活动依赖性突触可塑性。特别是，我们将检查之间的相互作用 内源性 BDNF 诱导的 eCB 释放和活性依赖性 eCB 释放在调节幅度和 兴奋性和抑制性突触的可塑性方向。这些研究将结合电生理学和 钙成像通过药理学和遗传学方法来操纵这些信号系统。我们将 还使用经过改造以表达常见人类单核苷酸的小鼠来检查这些信号传导相互作用 影响内源性 BDNF 或 anandamide 水平的多态性 (SNP)。重要的是，我们将执行 使用培养的人诱导多能干细胞 (iPSC) 衍生的神经元进行平行研究 携带这些相同 SNP 的个体。