title: Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels.
abstract: Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, β- and γ-actin, are expressed in dendritic spines, the specific contribution of γ-actin in the expression of synaptic plasticity is unknown. We show that synaptic γ-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg1 transcript are colocalized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates γ-actin, most likely cotranslationally at synaptic sites. Trim3(-/-) mice consequently have increased levels of γ-actin at hippocampal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of γ-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic γ-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity.
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Joerg
authors.initials: J
authors.lastname: Schreiber
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Végh
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Julia
authors.initials: J
authors.lastname: Dawitz
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Kroon
authors.affiliation: Sylics (Synaptologics BV), 1008 BA Amsterdam, Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Loos
authors.affiliation: Department of Molecular Neurogenetics, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Labonté
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Ka Wan
authors.initials: KW
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: Van Nierop
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Michiel T
authors.initials: MT
authors.lastname: Van Diepen
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, 3000 DR Rotterdam, Netherlands Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Science, 1105 BA Amsterdam, Netherlands.
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.affiliation: Department of Molecular Neurogenetics, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: Rhiannon M
authors.initials: RM
authors.lastname: Meredith
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, Netherlands ronald.van.kesteren@vu.nl.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Van Kesteren
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D000199:Actins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C586979:TRIM3 protein, mouse; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases