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    The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility

    Wall, MJ, Collins, DR, Chery, SL, Allen, ZD, Pastuzyn, ED, George, AJ, Nikolova, VD, Moy, SS, Philpot, BD, Shepherd, JD, Müller, J, Ehlers, MD, Mabb, AM and Corrêa, SAL (2018) The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility. Neuron, 98 (6). pp. 1124-1132. ISSN 0896-6273

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    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.

    Item Type: Article
    Peer-reviewed: Yes
    Date Deposited: 21 Oct 2019 14:42
    Publisher: Elsevier (Cell Press)
    Additional Information: This is an Open Access article published in Neuron, published by Elsevier, copyright The Author(s).
    Divisions: Faculties > Science and Engineering
    Subject terms: Animals, Mice, Cytoskeletal Proteins, Receptors, Metabotropic Glutamate, Receptors, AMPA, Nerve Tissue Proteins, RNA, Messenger, Cognition, Reversal Learning, Protein Transport, Neuronal Plasticity, Mutation, Time Factors, Long-Term Synaptic Depression, Ubiquitination, Gene Knock-In Techniques, Proteolysis, Spatial Learning, AMPA receptor trafficking, Arc/Arg3.1, Arc/Arg3.1 turnover, Barnes maze, cognitive flexibility, mGluR-LTD, reversal learning, synaptic plasticity, ubiquitin, Animals, Cognition, Cytoskeletal Proteins, Gene Knock-In Techniques, Long-Term Synaptic Depression, Mice, Mutation, Nerve Tissue Proteins, Neuronal Plasticity, Protein Transport, Proteolysis, RNA, Messenger, Receptors, AMPA, Receptors, Metabotropic Glutamate, Reversal Learning, Spatial Learning, Time Factors, Ubiquitination, 1109 Neurosciences, 1702 Cognitive Sciences, Neurology & Neurosurgery
    URI: https://e-space.mmu.ac.uk/id/eprint/624157
    DOI: https://doi.org/10.1016/j.neuron.2018.05.012
    ISSN 0896-6273
    e-ISSN 1097-4199

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