MDGAs help the brain lose its inhibitions

MDGAs help the brain lose its inhibitions S ynapse 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 neuro-developmental disorders; mutations in neu-roligin and neurexin family members, for example, are associated with autism and schizophrenia. Pettem et al. reveal that another family of proteins linked to these disorders regulates the function of neuro-ligins and neurexins in order to suppress the development of inhibitory synapses (1). Postsynaptic neuroligin proteins promote synaptogenesis by associating with neurexins on presynaptic membranes (2). Neuroligin-2, for instance, boosts the development of inhibitory synapses by binding to neurexin family members, and variants in both of these proteins are associated with either autism or schizophrenia. The neu-ronal proteins MDGA1 and MDGA2 have also been linked to these disorders (3–5), but their function in neuro-development remains unclear. Both MDGA proteins are localized to the plasma membrane via glycosylphos-phatidylinositol anchors, and their extracellular domains contain immunoglobulin-like folds and other motifs that are commonly found in cell adhesion molecules. " Based on that, Research Associate Daisaku Yoko-maku thought it might be interesting to study the possible function of MDGAs at synapses, " says Ann Marie Craig from the University of British Colum-bia in Vancouver, Canada. Craig and colleagues, led by Yokomaku (currently working for Otsuka Pharmaceutical in Japan) and Katherine Pettem (now an instructor at Camosun College in Victoria), investigated the function of MDGAs using co-culture assays, in which postsynaptic proteins like neuroligin-2 are expressed in nonneuronal cells and then tested for their ability to induce presyn-aptic differentiation in neighboring neurons. " Our fi rst thought was that MDGAs might promote synapse formation, " Craig explains. " But we didn't fi nd that. Instead, when MDGA1 was coexpressed with neuro-ligins, it inhibited the ability of neuroligin-2 to promote synapse development. " Pettem et al. found that MDGA1's extra-cellular immunoglobulin-like domains bound to neuroligin-2, blocking its association with neurexin. The same domains were suffi cient to inhibit neuroligin-2's syn-apse-promoting activity. In contrast, MDGA1 didn't show high affi nity binding to, or inhibit the function of, neuroligin-1, a member of the neuroligin family that promotes the development of excitatory synapses. This suggested that, by inhibiting neuroligin-2, MDGA1 might specifi cally suppress the development of inhibitory synapses, so Pettem and colleagues investigated MDGA1 function in cultured hippocampal neurons. " Overexpressing MDGA1 in neurons reduced the density of inhibitory …