Wall, Mark J., Collins, Dawn R., Chery, Samantha L., Allen, Zachary D., Pastuzyn, Elissa D., George, Arlene J., Nikolova, Viktoriya D., Moy, Sheryl S., Philpot, Benjamin D., Shepherd, Jason D., Müller, Jürgen, Ehlers, Michael D., Mabb, Angela M. and Corrêa, Sônia A. L. (2018) The temporal dynamics of Arc expression regulate cognitive flexibility. Neuron, 98 (6). pp. 1124-1132. doi:10.1016/j.neuron.2018.05.012 ISSN 1097-4199.

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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. Proteasome-dependent 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 knock-in 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:	Journal Article
Alternative Title:
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Nervous system -- Degeneration, Neuroplasticity, Cognition -- Physiological aspects
Journal or Publication Title:	Neuron
Publisher:	Cell Press
ISSN:	1097-4199
Official Date:	27 June 2018
Dates:	Date Event 27 June 2018 Published 31 May 2018 Available 4 May 2018 Accepted
Volume:	98
Number:	6
Page Range:	pp. 1124-1132
DOI:	10.1016/j.neuron.2018.05.012
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	10 May 2018
Date of first compliant Open Access:	4 June 2018
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID BB/H018344/1 [BBSRC] Biotechnology and Biological Sciences Research Council http://dx.doi.org/10.13039/501100000268 200646/Z/16/Z Wellcome Trust http://dx.doi.org/10.13039/100010269 2017-05-35 Whitehall Foundation http://dx.doi.org/10.13039/100001391 Laboratory start-up funds Georgia State University http://dx.doi.org/10.13039/100008545 NIH R01NS085093 National Institutes of Health http://dx.doi.org/10.13039/100000002 NIH R00 NS076364 National Institutes of Health http://dx.doi.org/10.13039/100000002 NIGMS R25GM109442 National Institutes of Health UNSPECIFIED
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