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

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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.