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

Laura J. Stoppel, Benjamin D. Auerbach, Rebecca K. Senter, Anthony R. Preza, Robert J. Lefkowitz, Mark F. Bear

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2807-2814
Number of pages8
JournalCell Reports
Volume18
Issue number12
DOIs
StatePublished - Mar 21 2017
Externally publishedYes

Keywords

  • autism
  • biased ligands
  • ERK
  • fragile X
  • intellectual disability
  • long-term depression
  • metabotropic glutamate receptors
  • mGluR5
  • synaptic protein synthesis
  • β-arrestin2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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