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

• Published in: The Journal of biological chemistry Vol. 299; no. 8; p. 104949
• Main Authors: Jong, Yuh-Jiin I., Izumi, Yukitoshi, Harmon, Steven K., Zorumski, Charles F., ÓMalley, Karen L.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2023; American Society for Biochemistry and Molecular Biology
• Subjects: calcium; extracellular signal-regulated kinase (ERK); G protein-coupled receptor (GPCR); metabotropic glutamate receptor 5 (mGlu5); mTOR complex (mTORC); neuron; signal transduction; AMPA; PS; eCB; neuron; Quis; CNQX; LFS; DHPG; mTOR complex (mTORC); calcium; CPCCOEt; signal transduction; FMRP; IO; RPS6; MPEP; PP2A; ACSF; metabotropic glutamate receptor 5 (mGlu5); ER; extracellular signal-regulated kinase (ERK); EAAT; DIV; MEK; Arc; CaMKII; mGlu5; rictor; G protein-coupled receptor (GPCR); GPCR; mTORC2; LTD; ERK
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2023.104949

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.