Dynamic organization of synaptic signaling by distinct neurexophilin/alpha neurexin complexes

突触通过特殊的突触前和突触后膜域在神经元之间传递信号。由于突触必须在整个生命过程中形成并适应刺激，它们的维持依赖于关键分子的协调传递。细胞黏附分子Neurexins(Nrxn)通过与结合伙伴协同作用在突触中发挥重要作用。然而，基于Nrxn的复合体在突触界面内外的动态行为和靶向性在很大程度上是未知的。我们已经提出了与Neurexophilins(Nxph)的络合物形成，Nxph是一个独特的神经肽样αNrxn特异性配体家族，它改变了突触的生理特性。初步数据显示，在不同的神经元亚群中表达的Nxph1和Nxph3对突触的影响是不同的。由于最近的研究表明，与Nxph1形成的复合体调节αNrxn的表面迁移率，Nxph1/AlphaNrxn和Nxph3/AlphaNrxn复合体可能以一种局部和功能上不同的方式改变突触界面上的信号和分子组成。在这里，我们想要比较这两个复合体的分子性质，并使用实时成像来研究它们在野生型和转基因小鼠的原代海马神经元中的突触靶向性。为了探索Nxph1/alphaNrxn和Nxph3/alphaNrxn复合体究竟如何影响突触功能，我们将分析这些培养物中神经递质的释放。因此，我们的项目强调对突触的动态观察，其中对突触分子组成的特定和局部重塑可能有助于确定终末亚群的重要功能属性。

Synapses mediate signaling between neurons through specialized pre- and postsynaptic membrane domains. Since synapses have to form and adapt to stimuli throughout life, their maintenance depends on the coordinated delivery of key molecules. The cell adhesion molecules neurexins (Nrxn) play essential roles in synapses by acting in concert with binding partners. However, the dynamic behavior and targeting of Nrxn-based complexes inside and outside of synaptic interfaces are largely unknown. We have proposed that complex formation with neurexophilins (Nxph), a unique family of neuropeptide-like alphaNrxn-specific ligands, changes the physiological properties of synapses. Preliminary data show that Nxph1 and Nxph3, expressed in distinct subpopulations of neurons, affect synapses differently. Since recent results revealed that complex formation with Nxph1 regulates the surface mobility of alphaNrxn, Nxph1/alphaNrxn and Nxph3/alphaNrxn complexes may modify signaling at and molecular composition of synaptic interfaces in a locally and functionally distinct way. Here we want to compare the molecular properties of these two complexes and use live imaging to investigate their synaptic targeting in transfected primary hippocampal neurons from wild-type and genetically modified mice. To explore how exactly Nxph1/alphaNrxn and Nxph3/alphaNrxn complexes affect synaptic function, we will analyze neurotransmitter release in these cultures. Thus, our project emphasizes a dynamic view of synapses in which specific and local remodelling of their molecular composition may serve to determine important functional properties of subpopulations of terminals.