Synapse development is promoted by a variety of cell adhesion molecules that connect neurons and organize synaptic proteins. Many of these adhesion molecules are linked to neurodevelopmental disorders; mutations in neuroligin and neurexin proteins, for example, are associated with autism and schizophrenia. According to a study in The Journal of Cell Biology, another family of proteins linked to these disorders regulates the function of neuroligins and neurexins in order to suppress the development of inhibitory synapses.
Like neurexins and neuroligins, the neuronal proteins MDGA1 and MDGA2 have been linked to autism and schizophrenia, but their function in neurodevelopment was unknown. Both MDGA proteins localize to the plasma membrane, and their extracellular domains are similar to those of cell adhesion molecules. On the other hand, postsynaptic neuroligin proteins are known to help synapses form by associating with neurexins on presynaptic membranes. Neuroligin-2 specifically boosts the development of inhibitory synapses, whereas neuroligin-1 promotes the development of excitatory synapses.
Ann Marie Craig and colleagues from the University of British Columbia investigated the function of MDGAs using co-culture assays, in which postsynaptic proteins like neuroligin-1 or -2 are expressed in non-neuronal cells and then tested for their ability to induce presynaptic differentiation in neighboring neurons. MDGA1 didn't promote synapse formation in these assays. Instead, it inhibited the ability of neuroligin-2 to promote synapse development. The researchers found that MDGA1's extracellular domains bound to neuroligin-2, blocking its association with neurexin. The same domains were sufficient to inhibit neuroligin-2's synapse-promoting activity. In contrast, MDGA1 didn't show high affinity binding to, or inhibit the function of, neuroligin-1. This suggested that, by inhibiting neuroligin-2, MDGA1 might specifically suppress the development of inhibitory synapses, so Craig and colleagues investigated MDGA1 function in cultured hippocampal neurons.