IGSF21 is an immunoglobulin superfamily protein that functions as a selective regulator of inhibitory synaptic development in the brain. IGSF21 localizes postsynaptically and promotes inhibitory presynaptic differentiation through trans-synaptic interaction with presynaptic neurexin2α (NRXN2) 1. This interaction is essential for proper synaptic organization and function; mice lacking IgSF21 show impaired inhibitory presynaptic organization in the hippocampal CA1 region and diminished GABA-mediated synaptic transmission, resulting in sensorimotor gating deficits 1. Alpha-neurexins utilize IgSF21 as a ligand to contribute to synaptic diversity and neural circuit activity fine-tuning 2. Beyond core synaptic function, IGSF21 has emerging disease relevance. Genetic variants in IGSF21-KLHDC7A are associated with diabetic retinopathy risk in type 2 diabetes; the CT-TT genotype of rs3007729 increased diabetic retinopathy development and correlated with elevated serum LDL concentrations 3. Single-nucleus transcriptomic analysis reveals increased IGSF21+ microglia abundance in Alzheimer's disease tissue, suggesting involvement in neuroinflammatory pathways 4. Additionally, proteomic evidence identifies IGSF21 as a potential therapeutic target for premature ovarian failure through Mendelian randomization analysis 5. These findings suggest IGSF21 functions beyond classical synaptic inhibition, implicating broader roles in neuroprotection and age-related diseases.