CASKIN1 is a multidomain scaffolding protein enriched in neural synapses that mediates synaptic organization and plasticity through multiple molecular mechanisms. Structurally, CASKIN1 contains a CASK interaction domain that binds the conserved peptide motif EEIWVLRK on the CASK calmodulin kinase domain, forming competing CASK/Caskin1/Velis complexes that associate with neurexin at presynaptic sites 1. Adjacent to this domain, tandem sterile α motif (SAM) domains form ionic-strength-sensitive helical polymers that can be decorated with CASK, contributing to active zone cytomatrix organization 2. Uniquely, CASKIN1 possesses an atypical SH3 domain lacking canonical aromatic residues for proline-rich peptide binding; instead, it selectively binds the signaling lipid mediator lysophosphatidic acid (LPA) with nanomolar affinity to LPA-containing membranes, potentially mediating membrane association 3, 4. CASKIN1 dysfunction is implicated in psychiatric disorders. A rare missense variant (D1204N) in the proline-rich region segregates with psychosis in families, causing transcriptomic changes in 368 genes related to neuronal differentiation and altered action potential frequency in iPSC-derived neurons 5. In major depressive disorder, elevated miR-21-5p downregulates CASKIN1 expression in excitatory neurons, reducing neural connectivity and synaptic plasticity 6. These findings establish CASKIN1 as a critical regulator of synaptic organization with direct relevance to psychiatric disease pathogenesis.