Striatal mGlu5-mediated synaptic plasticity is independently regulated by location-specific receptor pools and divergent signaling pathways
(2023) Journal of Biological Chemistry, 299 (8), art. no. 104949, .
Jong, Y.-J.I.a , Izumi, Y.b c , Harmon, S.K.a , Zorumski, C.F.a b c , ÓMalley, K.L.a
a Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
c The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO, United States
Abstract
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. © 2023 The Authors
Author Keywords
calcium; extracellular signal-regulated kinase (ERK); G protein-coupled receptor (GPCR); metabotropic glutamate receptor 5 (mGlu5); mTOR complex (mTORC); neuron; signal transduction
Funding details
National Institutes of HealthNIHMH101874, MH119197, MH122379, NS102783, P50 HD103525
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813
Document Type: Article
Publication Stage: Final
Source: Scopus