mGluRI targets microglial activation and selectively prevents neuronal cell engulfment through Akt and caspase dependent pathways

Metabotropic glutamate receptors (mGluRs) are expressed throughout the mammalian central nervous system and integrate a host of signal transduction pathways that determine cellular function, plasticity and injIury. Yet, one of the more unique regulatory functions of this family of GTP-binding proteins involves cytoprotection in the nervous system. Here, we demonstrate that activation of group I metabotropic glutamate receptors (mGluRIs) in primary hippocampal neurons not only provides intrinsic cellular protection for the maintenance of genomic DNA integrity, but also prevents inflammatory microglial activation and specific neuronal cell engulfment during free radical oxidative stress. Loss of cellular membrane asymmetry and exposure of membrane phosphatidylserine (PS) residues were necessary and sufficient to result in microglial activation and proliferation, since administration of an antibody to the PS receptor could block microglial activity. Through the continuous assessment of individual neurons in real time, activation of mGluRIs was documented to block neuronal PS exposure and prevented subsequent neuronal cell engulfment by microglia seeking "PS tagged" neurons. Furthermore, regulation of both cellular integrity and microglial activity by mGluRI activation was dependent upon the activation and phosphorylation of protein kinase B (Akt1), prevention of mitochondrial membrane depolarization with associated permeability transition pore complex formation, and the down regulation of caspase 9-like activity. Our work defines a significant role of mGluRIs for the modulation of cellular survival and inflammation in the nervous system during oxidative stress.