The Physio-Pathological Role of Group I Metabotropic Glutamate Receptors Expressed by Microglia in Health and Disease with a Focus on Amyotrophic Lateral Sclerosis

Microglia act as the immune guardians of the central nervous system (CNS), shifting between diverse activation states that can be either neuroprotective or neurotoxic. This review explores how Group I metabotropic glutamate receptors (mGlu1 and mGlu5) modulate these reactive phenotypes. While traditionally studied in neurons, this paper synthesizes emerging evidence that microglia-expressed mGluRs are key sensors that influence the progression of traumatic injuries and neurodegenerative disorders.

Group I mGluRs initiate complex intracellular signaling cascades involving phospholipase C, calcium mobilization, and protein kinases (such as PKC and MAPK). In many models, particularly after CNS trauma, the activation of mGluR5 in microglia appears to promote an anti-inflammatory, pro-reparative phenotype, thereby reducing neurotoxicity. However, the paper notes a 'dual role': in some chronic conditions, such as intracerebral hemorrhage, mGluR5 inhibition rather than activation has been associated with improved outcomes, likely due to differences in temporal intervention or specific cellular environments.

The authors emphasize that ALS is an unexplored frontier for these receptors. ALS is characterized by a non-cell-autonomous pathology where glial cells (microglia and astrocytes) significantly contribute to motor neuron death. In models like the SOD1-G93A mouse, mGluR1 and mGluR5 expression is altered, and their pharmacological or genetic modulation has shown promise in modifying disease progression. The review argues that current anti-inflammatory strategies in ALS have failed partly because they do not account for the dynamic, time-dependent shifts in microglia phenotypes, suggesting that fine-tuned mGluR modulation could be a superior approach.