β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X
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Author(s)
Auerbach, Benjamin D.
Lefkowitz, Robert J.
Stoppel, Laura Jane
Senter, Rebecca K
Preza, Anthony R.
Bear, Mark
Date Issued
March 2017
Journal
Cell Reports
Publisher
Elsevier
Citation
Stoppel, Laura J. et al. “β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.” Cell Reports 18, 12 (March 2017): 2807–2814 © 2017 The Author(s)
Version
Final published version
Abstract
Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local protein synthesis via activation of metabotropic glutamate receptor 5 (mGlu 5 ), yet how mGlu 5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu 5 -stimulated protein synthesis in the hippocampus and show that genetic reduction of β-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr1 −/y mouse model of FX. Importantly, reducing β-arrestin2 does not induce psychotomimetic activity associated with full mGlu 5 inhibitors and does not affect G q signaling. Thus, in addition to identifying a key requirement for mGlu 5 -stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu 5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.
MIT Department
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI of Published Version
https://doi.org/10.1016/J.CELREP.2017.02.075
