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|a dc
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|a Auerbach, Benjamin D.
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|a Picower Institute for Learning and Memory
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|a Stoppel, Laura Jane
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|a Senter, Rebecca K
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|a Preza, Anthony R.
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|a Bear, Mark
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|a Lefkowitz, Robert J.
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|a Stoppel, Laura Jane
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|a Senter, Rebecca K
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|a Preza, Anthony R.
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|a Bear, Mark
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|a β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X
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|b Elsevier,
|c 2017-09-29T19:28:31Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/111663
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|a 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.
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|a National Institutes of Health (U.S.) (Grant R21NS087225)
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|a National Institutes of Health (U.S.) (Grant 2R01HD046943)
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|a National Institutes of Health (U.S.) (Grant R01MH106469)
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|a Article
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|t Cell Reports
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