In this mini-review, we highlight the function of metabotropic glutamate receptors (mGluRs), in particular mGluR3 and mGluR5, in reactive astrocytes and relate these to three degenerative CNS diseases: multiple sclerosis, Alzheimer’s disease and Amyotrophic Lateral Sclerosis. The gene discussed is GRM5; the disease is early-onset autosomal dominant Alzheimer disease.