NeuroEV: Neuronal Extracellular Vesicles and microRNAs in BDNF-dependent hippocampal plasticity

细胞外小泡(EVS)是由所有细胞分泌的脂类包裹的小囊泡。小的EV，如外体和外体，已经成为几个生物系统中细胞间通信的新媒介。有几条证据支持EV作为突触可塑性的媒介的作用；即特定刺激后突触形态的变化：1)EV被证明调节突触的组成和密度；2)EV的跨突触传递在不同的环境中被证明；3)现在有许多EV在大脑中的功能性转移的例子，例如在神经元和神经胶质细胞或神经上皮之间。脑源性神经营养因子(BDNF)是突触可塑性的主要神经调节剂和介体。海马区的BDNF信号对学习记忆和应激恢复至关重要，在许多以认知功能下降为特征的障碍中观察到BDNF水平的降低。我的初步数据表明，经BDNF处理的神经元来源的EVS可以诱导幼稚海马神经元中兴奋性突触的成熟。这不是由于非特异性转移BDNF，而是依赖于特定的EV-microRNAs(MiRNAs)的活性，miRNAs是一种对神经元基因表达起关键调节作用的非编码小RNA。本项目的主要目标是：1)确定EV-miRNAs下游EV依赖的神经元突触形态发生的分子机制；2)使用允许瞬时抑制BDNF信号的小鼠模型，检测EV在体外BDNF依赖的可塑性中的特定贡献；以及3)表征EV通过神经元突触在体外和海马片中的传播。鉴于EVS在药物管理和作为生物标志物方面的前景，该项目不仅有助于我们对EV神经生物学的理解，还可能发现潜在的新方法来对抗以BDNF信号减少为特征的疾病。

Extracellular vesicles (EVs) are small lipid-enclosed vesicles secreted by all cells. Small EVs such as exosomes and ectosomes have emerged as novel mediators of inter-cellular communication in several biological systems. Several lines of evidence support a role for EVs as mediators of synaptic plasticity; that is changes in the morphology of synapses following a specific stimulus: 1) EVs were shown to modulate the composition and density of synapses; 2) the trans-synaptic transmission of EVs was demonstrated in different contexts; 3) there are now many examples of functional EV transfer in the brain, for instance between neurons and glia cells or neuroepithelia. Brain-derived neurotrophic factor (BDNF) is a major neuromodulator and mediator of synaptic plasticity. BDNF signaling in the hippocampus is crucial for learning and memory and stress resilience, and decreased levels of BDNF are observed in many disorders characterized by cognitive decline. My preliminary data demonstrate that EVs derived from neurons treated with BDNF can induce the maturation of excitatory synapses in naïve hippocampal neurons. This was not due to the non-specific transfer BDNF, but was rather dependent on the activity of specific EV-microRNAs(miRNAs), small non-coding RNAs that are crucial regulators of neuronal gene expression. The main objectives of this project are: 1) to identify the molecular mechanisms of EV-dependent neuronal synapse morphogenesis downstream EV-miRNAs, 2) to examine the specific contribution of EVs in BDNF-dependent plasticity in vitro using a mouse model that allows transient inhibition of BDNF signaling, and 3) to characterize the spreading of EVs via neuronal synapses in vitro and in hippocampal slices. Given the promising applications of EVs in drug administration and as biomarkers, this project may not only contribute to our understanding of EV neurobiology, it may also uncover potential new approaches for combating disorders characterized by reduced BDNF signaling.