突触是神经元之间建立联系、行使功能的高度特化的胞间连接，是构成脑神经信息处理和加工的巨大神经网络的基本单位。突触粘附分子NRXs和NLGs，介导突触前、后分子的募集和组装，优化神经网络，参与脑中所有的信息处理和加工过程，但机制不清。我们前期在研究果蝇DNlgs和DNrx中发现DNlgs存在蛋白翻译后加工现象与行为关联，提示Nlgs不仅以支架分子介导突触分子的募集和组装进而参与突触的形成，而且可能还作为信号分子通过特异性切割参与非神经递质的跨突触信号传递。本研究将综合应用动物模型和生物技术，进一步研究突触粘附复合体动态调控机制和在体功能，追踪NLG分子经切割产生的胞外段和胞内段的命运，探测它们是否发挥特定的信号传递作用，解析不同Nlgs分子的特异性加工的在体分子机制及其在神经发育和功能中的作用，阐明不同的神经环路中跨突触信号调节的可能范式，也为儿童孤独症的发病机制研究提供有价值的信息。

Synapses are highly specialized intercellular junctions that allow one neuron to communicate with another neuron or a target cell. They are basic units of information processing in huge neural networks of the brain. Synaptic adhesion molecules, NRXs and NLGs, connect presynaptic and postsynaptic neurons at synapses, mediate transsynaptic signal, and shape the properties of neural networks by specifying synaptic functions, however, the molecular mechanism remains to be elucidated. In previous and unpublished preliminary data on Drosophila Nlgs and Nrx from our laboratory, we found that DNlgs protein undergoes post-translational processing and this phenomenon is associated with Drosophila activity, suggesting that Nlgs not only serve as mediator of synaptic scaffold molecule assembly involving transsynaptic complex formation and synapse development, but may also act as non-synaptic neurotransmitter signaling molecules in synapse development and modulation following specific cleavage. Based on these data, here we propose that the proteolytic fragments of Nlgs transduce signals in synapse development and behavior. In this proposal, we will use Drosophila and mice as animal models, apply a combination of genetic, molecular, behavioral and electrophysiological analysis as well as live cell imaging, to further investigate the mechanisms underlying regulation of synaptic adhesion complex in vivo, to track the fate and function of extracellular and intracellular domains of NLGs generated by proteolysis, to analyze different roles of DNlgs in neural development and synaptic functions in vivo undergoing specific post-translational processing. Taken together, we would provide a general paradigm for the regulation of trans-synaptic signaling in different neural circuits, and valuable information for an insight into pathogenic mechanisms of autism spectrum disorders and other cognitive diseases.