Regulation of synaptic plasticity by BDNF-endocannabinoid interactions

项目摘要 本项目的目标是探索脑源性神经营养因子与神经营养因子之间相互作用的功能相关性。 内源性大麻素（eCB）在调节活动依赖性突触可塑性中的作用 新皮层和海马体。虽然有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， 关于潜在的突触相互作用。我们先前已经描述了eCB的突触效应 和BDNF在躯体感觉皮层2/3层和5层以及海马CA 1区的表达， 最近的研究表明，BDNF在皮层和海马抑制性突触的突触前作用， 由BDNF诱导的eCB从突触后锥体细胞的释放介导。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的易化作用。 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 在调节活动依赖性突触可塑性方面。特别是，我们将研究 内源性BDNF诱导的eCB释放和活性依赖性eCB释放在调节 兴奋性和抑制性突触可塑性的方向。这些研究将结合联合收割机电生理学和 钙成像与药理学和遗传学的方法来操纵这些信号系统。我们将 我还使用基因工程小鼠来检测这些信号相互作用， 基因多态性（SNP）影响内源性BDNF或大麻素水平。重要的是，我们将执行 使用培养的人诱导多能干细胞（iPSC）衍生的神经元进行的平行研究， 携带相同SNPs的个体。

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.