Striatal mGlu₅-mediated synaptic plasticity is independently regulated by location-specific receptor pools and divergent signaling pathways

Metabotropic glutamate receptor 5 (mGlu₅) is widely expressed throughout the central nervous system and is involved in neuronal function, synaptic transmission, and a number of neuropsychiatric disorders such as depression, anxiety, and autism. Recent work from this lab showed that mGlu₅ is one of a growing number of G protein-coupled receptors that can signal from intracellular membranes where it drives unique signaling pathways, including upregulation of extracellular signal-regulated kinase (ERK1/2), ETS transcription factor Elk-1, and activity-regulated cytoskeleton-associated protein (Arc). To determine the roles of cell surface mGlu₅ as well as the intracellular receptor in a well-known mGlu₅ synaptic plasticity model such as long-term depression, we used pharmacological isolation and genetic and physiological approaches to analyze spatially restricted pools of mGlu₅ in striatal cultures and slice preparations. Here we show that both intracellular and cell surface receptors activate the phosphatidylinositol-3-kinase–protein kinase B–mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, whereas only intracellular mGlu₅ activates protein phosphatase 2 and leads to fragile X mental retardation protein degradation and de novo protein synthesis followed by a protein synthesis–dependent increase in Arc and post-synaptic density protein 95. However, both cell surface and intracellular mGlu₅ activation lead to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA2 internalization and chemically induced long-term depression albeit via different signaling mechanisms. These data underscore the importance of intracellular mGlu₅ in the cascade of events associated with sustained synaptic transmission in the striatum.