Department of Biology, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France.
Curr Opin Neurobiol. 2019 Aug;57:71-80. doi: 10.1016/j.conb.2019.01.002. Epub 2019 Feb 14.
Synapse development depends on a dynamic balance between synapse promoters and suppressors. MDGAs, immunoglobulin superfamily proteins, negatively regulate synapse development through blocking neuroligin-neurexin interactions. Recent analyses of MDGA-neuroligin complexes revealed the structural basis of this activity and indicate that MDGAs interact with all neuroligins with differential affinities. Surprisingly, analyses of mouse mutants revealed a functional divergence, with targeted mutation of Mdga1 and Mdga2 elevating inhibitory and excitatory synapses, respectively, on hippocampal pyramidal neurons. Further research is needed to determine the synapse-specific organizing properties of MDGAs in neural circuits, which may depend on relative levels and subcellular distributions of each MDGA, neuroligin and neurexin. Behavioral deficits in Mdga mutant mice support genetic links to schizophrenia and autism spectrum disorders and raise the possibility of harnessing these interactions for therapeutic purposes.
突触发育取决于突触促进因子和抑制因子之间的动态平衡。MDGA 是免疫球蛋白超家族蛋白，通过阻断神经递质连接蛋白-神经递质受体相互作用来负调控突触发育。最近对 MDGA-神经递质连接蛋白复合物的分析揭示了这种活性的结构基础，并表明 MDGA 以不同的亲和力与所有神经递质连接蛋白相互作用。令人惊讶的是，对小鼠突变体的分析显示出功能上的差异，靶向突变 Mdga1 和 Mdga2 分别提高了海马锥体神经元上的抑制性和兴奋性突触。需要进一步研究来确定 MDGA 在神经回路中的突触特异性组织特性，这可能取决于每个 MDGA、神经递质连接蛋白和神经递质受体的相对水平和亚细胞分布。Mdga 突变体小鼠的行为缺陷支持了它们与精神分裂症和自闭症谱系障碍的遗传联系，并提出了利用这些相互作用进行治疗目的的可能性。
