Show simple item record

dc.contributor.advisorJoel Richter
dc.contributor.authorHien, Annie
dc.date2022-08-11T08:08:38.000
dc.date.accessioned2022-08-23T16:02:31Z
dc.date.available2022-08-23T16:02:31Z
dc.date.issued2020-07-22
dc.date.submitted2020-08-28
dc.identifier.doi10.13028/zhjn-x778
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31323
dc.description.abstractMutations in TSC2 cause the disorder tuberous sclerosis (TSC), which has a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD), but the identity of mRNAs responsive to mGluR-LTD signaling in the normal and TSC brain is largely unknown. We generated Tsc2+/- mice to model TSC autism and performed ribosome profiling to identify differentially expressed genes following mGluR-LTD in the normal and Tsc2+/- hippocampus. Ribosome profiling reveals that in Tsc2+/-mice, RNA-binding targets of Fragile X Mental Retardation Protein (FMRP) are increased. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD signaling failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in Tsc2+/- mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in the Tsc2+/- brain. These results suggest a molecular basis for bidirectional regulation of synaptic plasticity by TSC2 and FMRP. Furthermore, deficient mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2+/- mice.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjecttuberous sclerosis
dc.subjectfragile X syndrome
dc.subjectautism spectrum disorder
dc.subjectsynaptic plasticity
dc.subjectribosome profiling
dc.subjectMolecular and Cellular Neuroscience
dc.titleRegulation of Translation and Synaptic Plasticity by TSC2
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2106&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/1097
dc.legacy.embargo2020-08-28T00:00:00-07:00
dc.identifier.contextkey19176437
refterms.dateFOA2022-08-25T04:06:09Z
html.description.abstract<p>Mutations in <em>TSC2</em> cause the disorder tuberous sclerosis (TSC), which has a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD), but the identity of mRNAs responsive to mGluR-LTD signaling in the normal and TSC brain is largely unknown. We generated <em>Tsc2</em><sup>+/-</sup> mice to model TSC autism and performed ribosome profiling to identify differentially expressed genes following mGluR-LTD in the normal and <em>Tsc2</em><sup>+/-</sup> hippocampus. Ribosome profiling reveals that in <em>Tsc2<sup>+/-</sup></em>mice, RNA-binding targets of Fragile X Mental Retardation Protein (FMRP) are increased. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD signaling failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in <em>Tsc2</em><sup>+/-</sup> mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in the <em>Tsc2</em><sup>+/-</sup> brain. These results suggest a molecular basis for bidirectional regulation of synaptic plasticity by TSC2 and FMRP. Furthermore, deficient mGluR-regulated translation elongation contributes to impaired synaptic plasticity in <em>Tsc2<sup>+/-</sup></em> mice.</p>
dc.identifier.submissionpathgsbs_diss/1097
dc.contributor.departmentProgram in Molecular Medicine
dc.description.thesisprogramInterdisciplinary Graduate Program
dc.identifier.orcid0000-0002-9325-2287


Files in this item

Thumbnail
Name:
Hien_Annie_thesis_08282020_fin ...
Size:
11.64Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Licensed under a Creative Commons license
Except where otherwise noted, this item's license is described as Licensed under a Creative Commons license