Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression

Hou, Lingfei; Antion, Marcia D.; Hu, Daoying; Spencer, Corinne M.; Paylor, Richard; Klann, Eric

doi:10.1016/j.neuron.2006.07.005

Cited by 469Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchTreatment of Major Depression

Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression

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Hou, Lingfei, Antion, Marcia D., Hu, Daoying, Spencer, Corinne M., Paylor, Richard, Klann, Eric·2006·Neuron

DOI 10.1016/j.neuron.2006.07.005

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Abstract

Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.

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Proteasome inhibition alters basal synaptic transmission, long-term potentiation (LTP), and long-term depression (LTD) in mammals.
“In mammals, studies have shown that proteasome inhibition alters basal synaptic transmission, long-term potentiation (LTP), and long-term depression (LTD; Deng and Lei, 2007; Fonseca et al., 2006; Hou et al., 2006; Karpova et al., 2006).”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Hou et al., 2006
The Results (page not specified) show that proteasome inhibitors blocked the late phase of mGluR-dependent LTD in mouse hippocampal slices. The cited paper does not show that proteasome inhibition alters LTP or basal synaptic transmission; its comparison of basal transmission concerns mouse genotypes, not inhibitor treatment. (LLM, conf=0.88)
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Abnormally high Arc expression in Fmr1 knockout mice may be responsible for enhanced mGluR-LTD and may explain why their LTD is independent of new mRNA translation.
“This abnormally high level of Arc expression in Fmr1 knockout mice may be responsible for the enhanced mGluR–LTD observed in these animals and might explain, in part, why their LTD is independent of new mRNA translation62.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [62]

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Authors: Hou, L., Antion, M. D., Hu, D., Spencer, C. M., Paylor, R., & Klann, E.
Affiliations: Baylor College of Medicine (US)
Corresponding author: Klann, Eric
ORCID: Spencer, Corinne M.
Klann, Eric
Venue: Neuron
Publisher: Elsevier BV
Published: 2006-08
Volume: 51
Issue: 4
Pages: 441-454
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2006.07.005
OpenAlex: W2047636274
Cited by: 469
References: 63
Citations by year: 2026: 7 · 2025: 10 · 2024: 6 · 2023: 19 · 2022: 12 · 2021: 15 · 2020: 29 · 2019: 23 · 2018: 22 · 2017: 24 · 2016: 18 · 2015: 27 · 2014: 34 · 2013: 26 · 2012: 33
FWCI: 16.85
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2542 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (NS034007, NS047384)
FRAXA Research Foundation (HD024064)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords: FMRP, metabotropic glutamate receptors, translational regulation, ubiquitin-proteasome system, protein degradation, synaptic plasticity, hippocampus, proteasome inhibitors
MeSH terms: Animals, Animals, Newborn, Anisomycin, Benzoates, Dose-Response Relationship, Drug, Drug Interactions, Fluorescent Antibody Technique, Glycine, Leupeptins, Male, Methoxyhydroxyphenylglycol, Microtubule-Associated Proteins, Models, Biological, Protein Synthesis Inhibitors, Pyridines, RNA, Messenger, Protein Biosynthesis, Blotting, Western, Signal Transduction, Cysteine Proteinase Inhibitors, Receptors, Metabotropic Glutamate, Mice, Knockout, Excitatory Amino Acid Antagonists, Long-Term Synaptic Depression, Proteasome Endopeptidase Complex, Mice, Fragile X Messenger Ribonucleoprotein 1, In Vitro Techniques

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Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression

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