Pumping the brakes: suppression of synapse development by MDGA–neuroligin interactions

• Published in: Current opinion in neurobiology Vol. 57; pp. 71 - 80
• Main Authors: Connor, Steven A, Elegheert, Jonathan, Xie, Yicheng, Craig, Ann Marie
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2019; Elsevier
• Subjects: Animals; Biochemistry, Molecular Biology; Cell Adhesion Molecules, Neuronal; Dansyl Compounds; Galactosamine - analogs & derivatives; Life Sciences; Mice; Nerve Tissue Proteins; Synapses
• ISSN: 0959-4388; 1873-6882
• DOI: 10.1016/j.conb.2019.01.002

•MDGAs suppress synapse development by binding to neuroligin-occluding neurexin interaction.•MDGA1 and MDGA2 interact with all neuroligins with differential affinities in the physiological range.•In vivo loss of MDGA1 elevates inhibitory synapse numbers rendering networks resistant to excitation.•In vivo loss of MDGA2 elevates excitatory synapse numbers and strength.•MDGA1 also functions in basal progenitor aggregation in the subventricular zone. 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.