CBLN4 is a secreted synaptic organizer protein belonging to the C1q-TNF family that functions as a trans-synaptic signaling molecule. Structurally similar to cerebellin 1 (CBLN1) but with distinct binding properties, CBLN4 binds to neurexin-1β and acts as a DCC ligand in axon guidance 1. CBLN4 is essential for the formation and maintenance of inhibitory GABAergic synapses, particularly those made by somatostatin-positive interneurons, and its expression is controlled by the transcription factor Hes1 downstream of nerve growth factor signaling 2. The protein interacts with GluD1 glutamate receptors to organize synapses 3, with structural analyses revealing that neurexin binding occurs through the N-terminal region rather than the GluD2-binding site 4. Functionally, CBLN4 enhances GABAergic synaptic transmission and neuronal resistance to amyloid-β toxicity, suggesting neuroprotective properties relevant to neurodegeneration 2. In disease contexts, CBLN4 is downregulated in early Alzheimer's disease pathology 5 and serves as a biomarker for frontotemporal lobar degeneration with TDP pathology 6. CBLN4 expression also increases during temporomandibular joint disease progression 7.