Program in Molecular Medicine; Graduate School of Biomedical Sciences, Medical Scientist Training Program
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Molecular Biology | Nervous System Diseases | Neuroscience and Neurobiology
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.
TSC2, tuberous sclerosis, FMRP, synaptic plasticity
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DOI of Published Version
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
Hien A, Molinaro G, Liu B, Huber KM, Richter JD. (2020). Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP. Open Access Publications by UMMS Authors. https://doi.org/10.1186/s13229-020-00384-9. Retrieved from https://escholarship.umassmed.edu/oapubs/4427
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This work is licensed under a Creative Commons Attribution 4.0 License.