The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Synaptic adhesion molecules are believed to be important for various steps in synapse formation, elimination and refinement. Recent screens to identify the synaptogenic molecules in the artificial synapse formation assays have uncovered that Slit- and Trk-like proteins (Slitrks), a leucine-rich repeat (LRR)-containing neuronal transmembrane molecules composed of six members, induce presynaptic differentiation in cultured neurons. My talk will be composed of two parts on Slitrks and their ligands, leukocyte-antigen related receptor protein tyrosine phosphatases (LAR-RPTPs). In the first story of my talk, data from a series of gain-of-function and loss-of-function approaches will be presented to address whether Slitrks are critical for excitatory and inhibitory synapse functions. In addition, extensive binding data and artificial synapse-formation assays demonstrated that individual members of LAR-RPTPs are required for the synaptogenic activities of Slitrks toward distinct synapse types in an isoform-dependent manner. In the second part of my talk, the extensive structure-functional data will be discussed, starting with X-ray crystallography for Slitrk1/PTPδ complex, to pinpoint key residues involved in the interaction. Moreover, negative electron microscopy, biophysical and biochemical data will be presented to address how Slitrks interact with LAR-RPTPs. Finally, I will show the data that lateral multimerization of Slitrks, together with direct binding to LAR-RPTPs, is required for their synaptogenic activity in inducing presynaptic differentiation. Collectively, these results postulate that combinatorial interactions of Slitrks, together with LAR-RPTPs, maintain synapse formation to coordinate excitatory-inhibitory balance.