Moreover, exploiting a combination of mGlu5 and mGlu1 receptor NAMs, which would reduce excitatory transmission and glia reactivity, and mGluR3 PAMs, able to induce the production of neurotrophic factors, could represent an even more intriguing opportunity to reduce MN degeneration and glia reactivity in ALS. This evidence concerns the gene GRM5 and amyotrophic lateral sclerosis.