ß-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X

• Main Authors: Auerbach, Benjamin D. (Author), Lefkowitz, Robert J. (Author), Stoppel, Laura Jane (Contributor), Senter, Rebecca K (Contributor), Preza, Anthony R. (Contributor), Bear, Mark (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences (Contributor), Picower Institute for Learning and Memory (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2017-06-21T20:51:26Z.
• Subjects: Article
• Online Access: Get fulltext

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[subscript 5]), yet how mGlu[subscript 5] couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu[subscript 5]-stimulated protein synthesis in the hippocampus and show that genetic reduction of β-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr[superscript 1−/y] mouse model of FX. Importantly, reducing β-arrestin2 does not induce psychotomimetic activity associated with full mGlu[subscript 5] inhibitors and does not affect G[subscript q] signaling. Thus, in addition to identifying a key requirement for mGlu[subscript 5]-stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu[subscript 5] offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.
National Institutes of Health (U.S.) (Grant R21NS087225)
National Institutes of Health (U.S.) (Grant 2R01HD046943)
National Institutes of Health (U.S.) (Grant R01MH106469)
National Institutes of Health (U.S.) (Grant T32MH074249)
FRAXA Research Foundation (Postdoctoral Fellowship)