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    The temporal dynamics of Arc expression regulate cognitive flexibility

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    Publication date
    2018-06
    Author
    Wall, M.J.
    Collins, D.R.
    Chery, S.L.
    Allen, Z.D.
    Pastuzyn, E.D.
    George, A.J.
    Nikolova, V.D.
    Moy, S.S.
    Philpot, B.D.
    Shepherd, J.D.
    Muller, Jurgen
    Ehlers, M.D.
    Mabb, A.M.
    Corrêa, Sonia A.L.
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    Keyword
    Arc/Arg3.1
    Arc/Arg3.1 turnover
    AMPA receptor trafficking
    Synaptic plasticity
    mGluR-LTD
    Barnes maze
    Reversal learning
    Cognitive flexibility
    Ubiquitin
    Rights
    ©2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
    Peer-Reviewed
    Yes
    
    Metadata
    Show full item record
    Abstract
    Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasomedependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.
    URI
    http://hdl.handle.net/10454/16201
    Version
    Published version
    Citation
    Wall MJ, Collins DR, Chery SL et al (2018) The temporal dynamics of Arc expression regulate cognitive flexibility. Neuron. 98(6): 1124-1132.e7
    Link to publisher’s version
    https://doi.org/10.1016/j.neuron.2018.05.012
    Type
    Article
    Collections
    Life Sciences Publications

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