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

基本信息

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
项目类别：
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

项目摘要

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 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，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。