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：
10056991
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/10056991
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

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.

项目摘要该项目的目的是探索脑衍生的神经营养性之间相互作用的功能相关性因子（BDNF）和内源性大麻素（ECB）调节活性依赖性突触可塑性新皮层和海马。尽管越来越多的证据证明了BDNF和ECB之间的串扰，但很少有关潜在突触相互作用的已知。我们以前已经表征了ECB的突触效应第2/3层和体感皮质的第5层以及海马的CA1区域的BDNF，我们最近表明，BDNF对皮质和海马抑制突触的突触前作用是由BDNF诱导的ECB从突触后锥体细胞中释放而介导。我们还发现 BDNF导致ECB在兴奋性突触下释放，并且该欧洲央行信号会减轻直接促进性 BDNF在这些突触中的影响。我们现在准备探索这些互动的功能相关性在调节活动依赖性突触可塑性中。特别是，我们将研究内源性BDNF诱导的欧洲央行释放和活动依赖性欧洲央行释放在调节大小和兴奋性和抑制突触的可塑性方向。这些研究将结合电生理学和钙成像采用药理和遗传方法来操纵这些信号系统。我们将还使用工程设计以表达常见人类单核苷酸的小鼠检查这些信号的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类诱导多能干细胞（IPSC）衍生的神经元产生的平行研究携带相同SNP的个人。