Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP
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RESEARCH
Ribosome profiling in mouse hippocampus: plasticity‑induced regulation and bidirectional control by TSC2 and FMRP Annie Hien1,2† , Gemma Molinaro3† , Botao Liu1, Kimberly M. Huber3* and Joel D. Richter1*
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. Background Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by benign tumor growth in multiple organs and neuropsychiatric symptoms. Individuals with TSC have an increased incidence of seizures (~ 90%), *Correspondence: [email protected]; Joel. [email protected] † Annie Hien and Gemma Molinaro contributed equally to this work 1 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA 3 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Full list of author information is available at the end of the article
intellectual disability (~ 50%), and autism (~ 50%) [1]. Disrupted neuronal circuitry likely underlies many neuropathologies in TSC because individuals with an anatomically normal brain can still present substantial developmental delay, intellectual disability, and autism. More direct evidence for impaired neuronal connectivity is derived from mouse models of the disorder, which display hyperexcitability, aberrant synaptic plasticity, and altered dendritic spine morphology [2, 3]. TSC is caused by loss-of-function mutations
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