Regulation of Translation and Synaptic Plasticity by TSC2
dc.contributor.advisor | Joel Richter | |
dc.contributor.author | Hien, Annie | |
dc.date | 2022-08-11T08:08:38.000 | |
dc.date.accessioned | 2022-08-23T16:02:31Z | |
dc.date.available | 2022-08-23T16:02:31Z | |
dc.date.issued | 2020-07-22 | |
dc.date.submitted | 2020-08-28 | |
dc.identifier.doi | 10.13028/zhjn-x778 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/31323 | |
dc.description.abstract | Mutations 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.iso | en_US | |
dc.rights | Licensed under a Creative Commons license | |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | |
dc.subject | tuberous sclerosis | |
dc.subject | fragile X syndrome | |
dc.subject | autism spectrum disorder | |
dc.subject | synaptic plasticity | |
dc.subject | ribosome profiling | |
dc.subject | Molecular and Cellular Neuroscience | |
dc.title | Regulation of Translation and Synaptic Plasticity by TSC2 | |
dc.type | Doctoral Dissertation | |
dc.identifier.legacyfulltext | https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2106&context=gsbs_diss&unstamped=1 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/gsbs_diss/1097 | |
dc.legacy.embargo | 2020-08-28T00:00:00-07:00 | |
dc.identifier.contextkey | 19176437 | |
refterms.dateFOA | 2022-08-25T04:06:09Z | |
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.submissionpath | gsbs_diss/1097 | |
dc.contributor.department | Program in Molecular Medicine | |
dc.description.thesisprogram | Interdisciplinary Graduate Program | |
dc.identifier.orcid | 0000-0002-9325-2287 |