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

Publication date: 21 March 2017
Source:Cell Reports, Volume 18, Issue 12
Author(s): Laura J. Stoppel, Benjamin D. Auerbach, Rebecca K. Senter, Anthony R. Preza, Robert J. Lefkowitz, Mark F. Bear
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 β-arrestin2 mediates mGlu5-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 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 β-arrestin2-biased negative modulators of mGlu5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.

Graphical abstract

Teaser

Stoppel et al. find that β-arrestin2 is a critical link between mGlu5 and activity-dependent neuronal protein synthesis. Reducing β-arrestin2 levels corrects many synaptic and cognitive deficits in a mouse model of fragile X.


http://ift.tt/2n68V4g