The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility

• DOI: 10.1016/j.neuron.2018.05.012
• Publication Date: 2018-05-31T23:39:01Z
• Authors: Mark J. Wall; Dawn R. Collins; Samantha L. Chery; Zachary D. Allen; Elissa D. Pastuzyn; Arlene J. George; Viktoriya D. Niko...; Sheryl S. Moy; Benjamin D. Philpot; Jason D. Shepherd; Jürgen Müller; Michael D. Ehlers; Angela M. Mabb; Sonia A.L. Corrêa
• Keywords: Time Factors; Arc/Arg3.1 turnover; 1702 Cognitive Sciences; Spatial Learning; Nerve Tissue Proteins; Reversal Learning; 612; Cognitive flexibility; Receptors, Metabotropic Glutamate; cognitive flexibility; Synaptic plasticity; Barnes maze; Article; Mice; 03 medical and health sciences; Cognition; Arc/Arg3.1; Reversal learning; ubiquitin; Animals; Gene Knock-In Techniques; RNA, Messenger; Receptors, AMPA; mGluR-LTD; 0303 health sciences; synaptic plasticity; Neurology & Neurosurgery; AMPA receptor trafficking; Neuronal Plasticity; Ubiquitin; Long-Term Synaptic Depression; Ubiquitination; Cytoskeletal Proteins; Protein Transport; Mutation; Proteolysis; reversal learning; RC0321; 1109 Neurosciences

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.