UMMS Affiliation

Program in Molecular Medicine; Graduate School of Biomedical Sciences, Medical Scientist Training Program

Publication Date

2020-10-14

Document Type

Article

Disciplines

Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Molecular Biology | Nervous System Diseases | Neuroscience and Neurobiology

Abstract

BACKGROUND: Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with 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) and behavior, but the identity of mRNAs responsive to mGluR-LTD signaling is largely unknown.

METHODS: We utilized Tsc2(+/-) mice as a mouse model of TSC and prepared hippocampal slices from these animals. We induced mGluR-LTD synaptic plasticity in slices and processed the samples for RNA-seq and ribosome profiling to identify differentially expressed genes in Tsc2(+/-) and following mGluR-LTD synaptic plasticity.

RESULTS: Ribosome profiling reveals that in Tsc2(+/-) mouse hippocampal slices, the expression of several mRNAs was dysregulated: terminal oligopyrimidine (TOP)-containing mRNAs decreased, while FMRP-binding targets increased. Remarkably, we observed the opposite changes of FMRP binding targets in Fmr1(-/y) hippocampi. 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 failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in TSC mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in TSC mice.

CONCLUSION: These results suggest a molecular basis for bidirectional regulation of synaptic plasticity and behavior by TSC2 and FMRP. Our study also suggests that altered mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2(+/-) mice.

Keywords

TSC2, tuberous sclerosis, FMRP, synaptic plasticity

Rights and Permissions

Copyright © The Author(s) 2020. Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

DOI of Published Version

10.1186/s13229-020-00384-9

Source

Hien A, Molinaro G, Liu B, Huber KM, Richter JD. Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP. Mol Autism. 2020 Oct 14;11(1):78. doi: 10.1186/s13229-020-00384-9. PMID: 33054857; PMCID: PMC7556950. Link to article on publisher's site

Journal/Book/Conference Title

Molecular autism

Related Resources

Link to Article in PubMed

PubMed ID

33054857

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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