Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

Schreiber, Joerg; Végh, Marlene J.; Dawitz, Julia; Kroon, Tim; Loos, Maarten; Labonté, Dorthe; Li, Ka Wan; Nierop, Pim van; Diepen, Michiel van; Zeeuw, Chris I. De; Kneussel, Matthias; Meredith, Rhiannon M.; Smit, August B.; Kesteren, Ronald E. van

doi:10.1083/jcb.201506048

Cited by 27 publications

(23 citation statements)

References 74 publications

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“…For analysis of the images and quantification of synaptic GluA2 expression the Columbus image storage and data analysis system (PerkinElmer; Waltham, MA) was used. The experiment was independently replicated ( Schreiber et al, 2015 ) with a similar set-up from a different culture using independent sets of animals, and the resulting 2 × 5 wells were taken as the final n-number.…”

Section: Methodsmentioning

confidence: 99%

The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

Schmitz

Klaassen

Ruiperez-Alonso

et al. 2017

eLife

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Glutamatergic synapses rely on AMPA receptors (AMPARs) for fast synaptic transmission and plasticity. AMPAR auxiliary proteins regulate receptor trafficking, and modulate receptor mobility and its biophysical properties. The AMPAR auxiliary protein Shisa7 (CKAMP59) has been shown to interact with AMPARs in artificial expression systems, but it is unknown whether Shisa7 has a functional role in glutamatergic synapses. We show that Shisa7 physically interacts with synaptic AMPARs in mouse hippocampus. Shisa7 gene deletion resulted in faster AMPAR currents in CA1 synapses, without affecting its synaptic expression. Shisa7 KO mice showed reduced initiation and maintenance of long-term potentiation of glutamatergic synapses. In line with this, Shisa7 KO mice showed a specific deficit in contextual fear memory, both short-term and long-term after conditioning, whereas auditory fear memory and anxiety-related behavior were normal. Thus, Shisa7 is a bona-fide AMPAR modulatory protein affecting channel kinetics of AMPARs, necessary for synaptic hippocampal plasticity, and memory recall.

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Section: Methodsmentioning

confidence: 99%

The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

Schmitz

Klaassen

Ruiperez-Alonso

et al. 2017

eLife

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“…The UPS targets proteins for proteolysis through the conjugation of ubiquitin to substrates, which is coordinated by E3s ( 16 ). INO80 was previously identified as a substrate of TRIM3, an E3 that has been implicated in hippocampal synaptic plasticity and memory ( 21 ). Following extended-access cocaine self-administration, we found a decrease in TRIM3 protein expression in NAc P1 fractions on AD30 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, viral-mediated manipulation of INO80 bidirectionally mediated the expression of cocaine craving on AD30. We then examined E3 ubiquitin ligase (E3) tripartite motif-containing protein 3 (TRIM3), of which INO80 is a substrate ( 21 ). We found that TRIM3 protein expression and interaction with INO80 are decreased on AD30, indicating that the ubiquitin-proteasomal regulation of INO80 is impaired during prolonged abstinence from cocaine.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving

et al. 2019

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Neuroadaptations in the nucleus accumbens (NAc) underlie cue-induced cocaine craving that intensifies (“incubates”) during abstinence and is believed to contribute to persistent relapse vulnerability. Changes in gene expression often govern perpetual behavioral abnormalities, but epigenetic plasticity during prolonged abstinence from drug exposure is poorly understood. We examined how E3 ubiquitin ligase TRIM3 dysregulates chromatin remodeler INO80 to mediate cocaine craving during prolonged abstinence. We found that INO80 expression increased in the NAc on abstinence day 30 (AD30) but not on AD1 following cocaine self-administration. Furthermore, TRIM3, which mediates degradation of INO80, was reduced on AD30, along with TRIM3-INO80 interaction. Viral-mediated gene transfer of INO80 or TRIM3 governed cocaine craving during prolonged abstinence. Lastly, chromatin immunoprecipitation followed by massively parallel DNA sequencing identified INO80-mediated transcriptional regulation of predicted pathways associated with cocaine plasticity. Together, these results demonstrate a novel ubiquitin-proteasomal-epigenetic mechanism by which TRIM3-INO80 mediates cocaine craving during prolonged abstinence.

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“…Also in sensory neurons, GFP mRNA containing the 3′ UTR of Actβ translocates into axons, whereas the 3′ UTR of Actγ cannot drive the transport of GFP mRNA into axons (Willis et al, 2007Donnelly et al, 2011). However, in more recent studies using sensitive techniques, mRNAs for Actγ could be detected in hippocampal synapse-enriched fractions, and mRNAs for both Actα and Actγ were detected in neuropil and somata layers of the CA1 region of the hippocampus (Cajigas et al, 2012;Schreiber et al, 2015). Knockout mouse models for the different actin isoforms have provided evidence both for their specific and overlapping cellular functions.…”

Section: Discussionmentioning

confidence: 99%

Differential roles of α-, β-, and γ-actin in axon growth and collateral branch formation in motoneurons

Moradi

Sivadasan

Saal

et al. 2017

Journal of Cell Biology

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Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

Cited by 27 publications

References 74 publications

The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving

Differential roles of α-, β-, and γ-actin in axon growth and collateral branch formation in motoneurons

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