ß-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X
Author(s)Auerbach, Benjamin D.; Lefkowitz, Robert J.; Stoppel, Laura Jane; Senter, Rebecca K; Preza, Anthony R.; Bear, Mark; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and Memory
Stoppel, Laura J. et al. “ß-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.” Cell Reports 18.12 (2017): 2807–2814.
Final published version