title: Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty.
abstract: Exposure to a novel environment enhances the extinction of contextual fear. This has been explained by tagging of the hippocampal synapses used in extinction, followed by capture of proteins from the synapses that process novelty. The effect is blocked by the inhibition of hippocampal protein synthesis following the novelty or the extinction. Here, we show that it can also be blocked by the postextinction or postnovelty intrahippocampal infusion of the NMDA receptor antagonist 2-amino-5-phosphono pentanoic acid; the inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), autocamtide-2-related inhibitory peptide; or the blocker of L-voltage-dependent calcium channels (L-VDCCs), nifedipine. Inhibition of proteasomal protein degradation by β-lactacystin has no effect of its own on extinction or on the influence of novelty thereon but blocks the inhibitory effects of all the other substances except that of rapamycin on extinction, suggesting that their action depends on concomitant synaptic protein turnover. Thus, the tagging-and-capture mechanism through which novelty enhances fear extinction involves more molecular processes than hitherto thought: NMDA receptors, L-VDCCs, CaMKII, and synaptic protein turnover.
authors.affiliation: National Institute of Translational Neuroscience, National Research Council of Brazil, and Memory Center, Brain Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90610-000, Brazil.
authors.forename: Jociane
authors.initials: J
authors.lastname: de Carvalho Myskiw
authors.forename: Cristiane Regina Guerino
authors.initials: CR
authors.lastname: Furini
authors.forename: Fernando
authors.initials: F
authors.lastname: Benetti
authors.forename: Ivan
authors.initials: I
authors.lastname: Izquierdo
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000841:Anisomycin / Q000008:administration & dosage / Q000494:pharmacology; D001522:Behavior, Animal; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D003214:Conditioning, Classical; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005239:Fear; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D047428:Protein Kinase Inhibitors; D025801:Ubiquitin; C067713:lactacystin; D000841:Anisomycin; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus; D000111:Acetylcysteine
keywords: fear conditioning; hippocampus; memory; synaptic plasticity; synaptic tagging and capture