Show simple item record

dc.contributor.authorAuerbach, Benjamin D.
dc.contributor.authorLefkowitz, Robert J.
dc.contributor.authorStoppel, Laura Jane
dc.contributor.authorSenter, Rebecca K
dc.contributor.authorPreza, Anthony R.
dc.contributor.authorBear, Mark
dc.date.accessioned2017-09-29T19:28:31Z
dc.date.available2017-09-29T19:28:31Z
dc.date.issued2017-03
dc.date.submitted2017-01
dc.identifier.issn2211-1247
dc.identifier.urihttp://hdl.handle.net/1721.1/111663
dc.description.abstractSynaptic 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 5 ), yet how mGlu 5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu 5 -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 mGlu 5 inhibitors and does not affect G q signaling. Thus, in addition to identifying a key requirement for mGlu 5 -stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu 5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant R21NS087225)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant 2R01HD046943)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant R01MH106469)en_US
dc.publisherElsevieren_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/J.CELREP.2017.02.075en_US
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.sourcePublisheren_US
dc.titleβ-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile Xen_US
dc.typeArticleen_US
dc.identifier.citationStoppel, Laura J. et al. “β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.” Cell Reports 18, 12 (March 2017): 2807–2814 © 2017 The Author(s)en_US
dc.contributor.departmentPicower Institute for Learning and Memoryen_US
dc.contributor.mitauthorStoppel, Laura Jane
dc.contributor.mitauthorSenter, Rebecca K
dc.contributor.mitauthorPreza, Anthony R.
dc.contributor.mitauthorBear, Mark
dc.relation.journalCell Reportsen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2017-09-27T14:23:51Z
dspace.orderedauthorsStoppel, Laura J.; Auerbach, Benjamin D.; Senter, Rebecca K.; Preza, Anthony R.; Lefkowitz, Robert J.; Bear, Mark F.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-6673-4988
mit.licensePUBLISHER_CCen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record