Paralogs of Slitrk cell adhesion molecules configure excitatory synapse specificity via distinct cellular mechanisms

Vertebrate neural circuit properties are shaped by synaptic cell adhesion molecules (CAMs). CAMs often have multiple paralogs but the possible redundancy of such paralogs remains underexplored. Using circuit-specific conditional knockout (cKO) mice deficient for Slitrk1 and Slitrk2, we show that these paralogs lack specific laminar expression in mature hippocampal neurons but divergently guide the specificity of neural circuits in distinct hippocampal subfields. Slitrk1 and Slitrk2 regulate distinct facets of excitatory synaptic properties in a microcircuit-dependent manner through binding to LAR-RPTPs, and additionally in the case of Slitrk2, through binding to PDZ domain-containing proteins and TrkB. Analyses of Slitrk2 V89M knock-in mice revealed that this schizophrenia-associated substitution acts uniquely as a loss-of-function mutation in some microcircuits to impair excitatory synaptic transmission, asynchronous release, and spatial reference memory. These findings demonstrate that even structurally and biochemically similar synaptic CAMs can play distinct roles in specifying neural circuit architecture.