HOMER1 is a postsynaptic density scaffolding protein that serves as a critical nexus for glutamatergic synaptic signaling and neuroinflammation. Its primary function involves binding and cross-linking cytoplasmic regions of metabotropic glutamate receptors (GRM1, GRM5) with intracellular calcium release channels (ITPR1), coupling surface receptors to intracellular calcium mobilization and regulating synaptic plasticity 1. HOMER1 exists as multiple isoforms with distinct functions: constitutive isoforms (Homer1b/c) stabilize receptor complexes and promote long-term potentiation, while the activity-induced Homer1a isoform acts as a dominant negative regulator, modulating stress responses and synaptic remodeling 1. Beyond glutamatergic signaling, HOMER1 negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway [UniProt]. HOMER1 dysregulation is implicated in multiple pathological conditions: after intracerebral hemorrhage, Homer1 overexpression promotes conversion of pro-inflammatory A1 astrocytes to neuroprotective A2 astrocytes through MAPK pathway inhibition 2. HOMER1 alterations are associated with psychiatric disorders including depression, psychosis, and addiction 3, and represent a common molecular signature in comorbid epilepsy-depression 4. A HOMER1 SNP (rs3822568) correlates with sleep architecture alterations, suggesting roles in sleep-wake regulation 5. Additionally, HOMER1 expression is linked to chemotherapy resistance in polyploid cancer cells 6, indicating broader pathophysiological significance beyond neural tissue.