| First Author | Stoppel LJ | Year | 2017 |
| Journal | Cell Rep | Volume | 18 |
| Issue | 12 | Pages | 2807-2814 |
| PubMed ID | 28329674 | Mgi Jnum | J:251185 |
| Mgi Id | MGI:6103653 | Doi | 10.1016/j.celrep.2017.02.075 |
| Citation | Stoppel LJ, et al. (2017) beta-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X. Cell Rep 18(12):2807-2814 |
| abstractText | 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 (mGlu5), yet how mGlu5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that beta-arrestin2 mediates mGlu5-stimulated protein synthesis in the hippocampus and show that genetic reduction of beta-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr1(-/y) mouse model of FX. Importantly, reducing beta-arrestin2 does not induce psychotomimetic activity associated with full mGlu5 inhibitors and does not affect Gq signaling. Thus, in addition to identifying a key requirement for mGlu5-stimulated protein synthesis, these data suggest that beta-arrestin2-biased negative modulators of mGlu5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders. |
