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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
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.
Publication Date
2018-06
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©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/).
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Yes
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openAccess
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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.
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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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Article