Regulation of synaptic plasticity by BDNF-endocannabinoid interactions

项目总结 该项目的目标是探索脑源性神经营养之间相互作用的功能相关性。 脑源性神经营养因子(BDNF)和内源性大麻素(ECB)在脑内活性依赖突触可塑性调节中的作用 大脑皮层和海马体。尽管有越来越多的证据表明BDNF和ECB之间存在串扰，但几乎没有证据表明 已知的关于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在躯体感觉皮质的第2/3层和第5层以及海马区的CA1区，我们 最近的研究表明，脑源性神经营养因子在皮层和海马抑制性突触的突触前效应 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信号减轻了直接促进性 脑源性神经营养因子对这些突触的影响。我们现在准备探索这些相互作用的功能相关性 在调节活性依赖的突触可塑性方面。尤其是，我们将研究 内源性BDNF诱导的ECB释放和活性依赖的ECB释放调节 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 钙成像结合药理学和遗传学方法来操纵这些信号系统。我们会 也要用经过改造的表达普通人类单核苷酸的小鼠来研究这些信号相互作用。 影响内源性脑源性神经营养因子或花生胺水平的多态(SNP)。重要的是，我们将开展 利用培养的人诱导多能干细胞(IPSC)来源的神经元进行平行研究 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.