The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit-and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance.leucine-rich repeat | neuropsychiatic disorder | synaptic cell-adhesion

The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2-dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...