GRM5 encodes metabotropic glutamate receptor 5 (mGluR5), a G protein-coupled receptor that functions as an obligate dimer with a large extracellular ligand-binding domain linked to a 7-transmembrane domain 1. Upon glutamate binding, mGluR5 undergoes conformational changes that activate phosphatidylinositol-calcium second messenger systems, generating calcium-activated signaling crucial for synaptic plasticity and neural network regulation. mGluR5 is expressed ubiquitously throughout the brain, including in astrocytes and at synapses. Dysregulation of mGluR5 signaling contributes to multiple neurological conditions. In Alzheimer's disease, elevated astrocytic mGluR5 correlates with disease progression and promotes amyloid-β pathology through calcium hyperactivity that impairs Aβ uptake and degradation 2. GRM5 has been associated with attention-deficit/hyperactivity disorder pathogenesis 3. In fragile X syndrome, reducing GRM5 expression rescues seizures and behavioral phenotypes, indicating excessive mGluR5 signaling contributes to pathology 4. mGluR5 also participates in pain signaling and is targeted by selective antagonists like MPEP for inflammatory pain treatment 5. Additionally, GRM5 variants influence grazing behaviors in cattle and pain-related pharmacogenetics in humans 6, 7. These findings establish mGluR5 as a multifunctional regulator of synaptic function with relevance across neurodevelopmental, neurodegenerative, and pain disorders.