Uchigashima Motokazu, Cheung Amy, Futai Kensuke
Department of Cellular Neuropathology, Brain Research Institute, Niigata University, Niigata, Japan.
Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, United States.
Front Mol Neurosci. 2021 Oct 6;14:749164. doi: 10.3389/fnmol.2021.749164. eCollection 2021.
Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene.
化学突触为神经元之间的通讯以及整体脑功能提供了至关重要的基础。通过将用于突触前神经递质释放和突触后信号转导的紧密相邻的分子机制连接起来，特定回路和情境下的突触特性能够驱动动物行为的神经元计算。经由突触细胞粘附分子（CAMs）进行的跨突触信号传导是产生化学突触分子多样性的一种很有前景的机制。神经连接蛋白（Nlgns）作为突触后CAMs被发现，其能在突触间隙与突触前CAMs如神经纤毛蛋白（Nrxns）结合。在啮齿动物或人类中分别有四种（Nlgn1 - 4）或五种（Nlgn1 - 3、Nlgn4X和Nlgn4Y）异构体，其中Nlgn3在特定化学突触亚群中具有异质性表达和功能，并且与非综合征性自闭症谱系障碍（ASD）密切相关。多条证据表明，Nlgn3蛋白独特的表达和功能是由Nlgn3基因破坏导致的非综合征性ASD所特有的回路特异性功能障碍的基础。此外，最近的研究揭示了海马抑制性突触处Nlgn3蛋白输入细胞依赖性表达的分子机制，其中Nlgn3和Nrxn特定可变剪接异构体的跨突触信号传导起着关键作用。在这篇综述文章中，我们概述了关于Nlgn3的分子、解剖和生理学知识，重点关注哺乳动物Nlgn3的回路特异性功能及其潜在分子机制。这不仅将为特定Nlgn3介导的跨突触相互作用作为突触特异性分子编码提供新的见解，还将有助于更好地理解与Nlgn3基因功能受损相关的非综合征性ASD的病理生理基础。
