The amygdala NT3-TrkC pathway underlies inter-individual differences in fear extinction and related synaptic plasticity.

Autor: Masella G; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal., Silva F; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal., Corti E; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal., Azkona G; Department of Basic Psychological Processes and Their Development, School of Psychology, University of the Basque Country (UPV/EHU), San Sebastian, Spain., Madeira MF; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal., Tomé ÂR; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Department of Life Sciences, University of Coimbra, Coimbra, Portugal., Ferreira SG; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal., Cunha RA; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Faculty of Medicine, University of Coimbra, Coimbra, Portugal., Duarte CB; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Department of Life Sciences, University of Coimbra, Coimbra, Portugal., Santos M; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. mjpsantos@cnc.uc.pt.; Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal. mjpsantos@cnc.uc.pt.; Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. mjpsantos@cnc.uc.pt.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 May; Vol. 29 (5), pp. 1322-1337. Date of Electronic Publication: 2024 Jan 17.
DOI: 10.1038/s41380-024-02412-z
Abstrakt: Fear-related pathologies are among the most prevalent psychiatric conditions, having inappropriate learned fear and resistance to extinction as cardinal features. Exposure therapy represents a promising therapeutic approach, the efficiency of which depends on inter-individual variation in fear extinction learning, which neurobiological basis is unknown. We characterized a model of extinction learning, whereby fear-conditioned mice were categorized as extinction (EXT)-success or EXT-failure, according to their inherent ability to extinguish fear. In the lateral amygdala, GluN2A-containing NMDAR are required for LTP and stabilization of fear memories, while GluN2B-containing NMDAR are required for LTD and fear extinction. EXT-success mice showed attenuated LTP, strong LTD and higher levels of synaptic GluN2B, while EXT-failure mice showed strong LTP, no LTD and higher levels of synaptic GluN2A. Neurotrophin 3 (NT3) infusion in the lateral amygdala was sufficient to rescue extinction deficits in EXT-failure mice. Mechanistically, activation of tropomyosin receptor kinase C (TrkC) with NT3 in EXT-failure slices attenuated lateral amygdala LTP, in a GluN2B-dependent manner. Conversely, blocking endogenous NT3-TrkC signaling with TrkC-Fc chimera in EXT-success slices strengthened lateral amygdala LTP. Our data support a key role for the NT3-TrkC system in inter-individual differences in fear extinction in rodents, through modulation of amygdalar NMDAR composition and synaptic plasticity.
(© 2024. The Author(s).)
Databáze: MEDLINE
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