GluD1 at the synaptic crossroads: from domain structure to circuit dysfunction

For several decades, the glutamate delta-1 receptor (GluD1) has remained an enigmatic entity among ionotropic glutamate receptors (iGluRs), primarily due to its lack of classical ion channel activity. Recent advancements have redefined GluD1 as a multifunctional synaptic organizer, essential for the development, plasticity, and behavioral regulation of both excitatory and inhibitory circuits. In this review, we synthesize recent progress at the structural, molecular, and circuit levels to reconceptualize GluD1 as a pivotal signaling scaffold that functions through non-ionotropic mechanisms. We emphasize the modular architecture of GluD1, encompassing the amino-terminal domain, ligand-binding domain, transmembrane region, and C-terminal domain to elucidate how each component uniquely contributes to synaptic function. Evidence from genetic models and structural biology underscores GluD1's involvement in transsynaptic adhesion, ligand-dependent conformational signaling, and intracellular pathway modulation. Additionally, we discuss its emerging clinical significance, with GRID1 mutations associated with neurodevelopmental and psychiatric disorders, and recent findings implicating GluD1 dysfunction in chronic pain. Finally, we explore domain-specific therapeutic strategies, including peptide mimetics, synthetic organizers, and non-ionotropic modulators, positioning GluD1 as a promising target for circuit-level intervention in brain disorders.