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Neuron. 2018 Jun 27;98(6):1124-1132.e7. doi: 10.1016/j.neuron.2018.05.012. Epub 2018 May 31.

The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility.

Author information

1
School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK.
2
Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
3
Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA.
4
Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
5
Department of Psychiatry and the Carolina Institute for Developmental Disorders, University of North Carolina, Chapel Hill, NC 27599, USA.
6
Neuroscience Center, Department of Cell Biology & Physiology, and the Carolina Institute for Developmental Disorders, University of North Carolina, Chapel Hill, NC 27599, USA.
7
Bradford School of Pharmacy and Medical Sciences, University of Bradford, Bradford, BD7 1DP, UK.
8
Biogen, Cambridge, MA 02142, USA.
9
Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA. Electronic address: amabb@gsu.edu.
10
School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK; Bradford School of Pharmacy and Medical Sciences, University of Bradford, Bradford, BD7 1DP, UK. Electronic address: s.a.l.correa@bradford.ac.uk.

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 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.

KEYWORDS:

AMPA receptor trafficking; Arc/Arg3.1; Arc/Arg3.1 turnover; Barnes maze; cognitive flexibility; mGluR-LTD; reversal learning; synaptic plasticity; ubiquitin

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