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The temporal dynamics of Arc expression regulate cognitive flexibility

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.
... show 4 more
Publication Date
2018-06
End of Embargo
Supervisor
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
Open Access status
openAccess
Accepted for publication
04/05/2018
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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.
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
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Link to published version
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Article
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