Hippocampal CaMKII inhibition induces reactivation-dependent amnesia for extinction memory and causes fear relapse

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Andressa Radiske
Carla Miranda de Castro
Janine I. Rossato
Maria Carolina Gonzalez
Martín Cammarota
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[1] Federal University of Rio Grande do Norte,Memory Research Laboratory
[2] Edmond and Lily Safra International Institute of Neuroscience, Brain Institute
[3] Federal University of Rio Grande do Norte,Department of Biophysics and Pharmacology, Biosciences Center
[4] Federal University of Rio Grande do Norte,Department of Physiology, Biosciences Center
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Hippocampal GluN2B subunit-containing NMDAR (GluN2B-NMDAR) activation during recall destabilizes fear extinction memory, which must undergo brain-derived neurotrophic factor (BDNF)-dependent reconsolidation to persist. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a Ser/Thr protein kinase essential for hippocampus-dependent memory processing that acts downstream GluN2B-NMDAR and controls BDNF expression, but its participation in fear extinction memory reconsolidation has not yet been studied. Using a combination of pharmacological and behavioral tools, we found that in adult male Wistar rats, intra dorsal-CA1 administration of the CaMKII inhibitors autocamtide-2-related inhibitory peptide (AIP) and KN-93, but not of their inactive analogs scrambled AIP and KN-92, after fear extinction memory recall impaired extinction and caused GluN2B-NMDAR-dependent recovery of fear. Our results indicate that hippocampal CaMKII is necessary for fear extinction reconsolidation, and suggest that modulation of its activity around the time of recall controls the inhibition that extinction exerts on learned fear.
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