β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.
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 mGlu5couples 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-/ymouse model of FX. Importantly, reducing β-arrestin2 does not induce psychotomimetic activity associated with full mGlu5inhibitors and does not affect Gqsignaling. Thus, in addition to identifying a key requirement for mGlu5-stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu5offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Laura J
LJ
Stoppel
The Center for Hearing and Deafness, Department of Communicative Disorders and Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USA.
Benjamin D
BD
Auerbach
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Rebecca K
RK
Senter
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Anthony R
AR
Preza
Departments of Medicine and Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Robert J
RJ
Lefkowitz
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: mbear@mit.edu.
Mark F
MF
Bear
D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D005600:Fragile X Syndrome / Q000378:metabolism* / Q000628:therapy*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D017353:Gene Deletion; D006579:Heterozygote; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D015398:Signal Transduction; D000071560:beta-Arrestin 2 / Q000378:metabolism*
D016291:Dizocilpine Maleate; D048049:Extracellular Signal-Regulated MAP Kinases; D051860:Fragile X Messenger Ribonucleoprotein 1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D064529:Receptor, Metabotropic Glutamate 5; D000071560:beta-Arrestin 2
ERK; autism; biased ligands; fragile X; intellectual disability; long-term depression; mGluR5; metabotropic glutamate receptors; synaptic protein synthesis; β-arrestin2