title: Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear.
abstract: The inability to properly extinguish fear memories constitutes the foundation of several anxiety disorders, including panic disorder. Recent findings show that boosting prefrontal cortex synaptic plasticity potentiates fear extinction, suggesting that therapies that augment synaptic plasticity could prove useful in rescue of fear extinction impairments in this group of disorders. Previously, we reported that mice with selective deregulation of neurotrophic tyrosine kinase receptor, type 3 expression (TgNTRK3) exhibit increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Here we explore the specific role of neurotrophin 3 and its cognate receptor in the medial prefrontal cortex, and its involvement in fear extinction in a pathological context. In this study we combined molecular, behavioral, in vivo pharmacology and ex vivo electrophysiological recordings in TgNTRK3 animals during contextual fear extinction processes. We show that neurotrophin 3 protein levels are increased upon contextual fear extinction in wild-type animals but not in TgNTRK3 mice, which present deficits in infralimbic long-term potentiation. Importantly, infusion of neurotrophin 3 to the medial prefrontal cortex of TgNTRK3 mice rescues contextual fear extinction and ex vivo local application improves medial prefrontal cortex synaptic plasticity. This effect is blocked by inhibition of extracellular signal-regulated kinase phosphorylation through peripheral administration of SL327, suggesting that rescue occurs via this pathway. Our results suggest that stimulating neurotrophin 3-dependent medial prefrontal cortex plasticity could restore contextual fear extinction deficit in pathological fear and could constitute an effective treatment for fear-related disorders.
authors.affiliation: Systems Biology Programme, Centre for Genomic Regulation (CRG)/Barcelona Biomedical Research Park, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
authors.forename: Davide
authors.initials: D
authors.lastname: D'Amico
authors.affiliation: Systems Biology Programme, Centre for Genomic Regulation (CRG)/Barcelona Biomedical Research Park, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
authors.forename: Thomas
authors.identifier: 0000-0001-9209-9228
authors.initials: T
authors.lastname: Gener
authors.affiliation: Systems Biology Programme, Centre for Genomic Regulation (CRG)/Barcelona Biomedical Research Park, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
authors.forename: Maria Martínez
authors.initials: MM
authors.lastname: de Lagrán
authors.affiliation: Systems Neuroscience, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain.|Life & Medical Sciences, ICREA (Instituciò Catalana de Recerca i Estudis Avançats), Barcelona, Spain.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Sanchez-Vives
authors.affiliation: Systems Biology Programme, Centre for Genomic Regulation (CRG)/Barcelona Biomedical Research Park, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Santos
authors.affiliation: Systems Biology Programme, Centre for Genomic Regulation (CRG)/Barcelona Biomedical Research Park, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
authors.forename: Mara
authors.identifier: 0000-0003-0853-6865
authors.initials: M
authors.lastname: Dierssen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005239:Fear; D005260:Female; D017774:Long-Term Potentiation; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D020933:Neurotrophin 3 / Q000008:administration & dosage* / Q000502:physiology; D010698:Phobic Disorders / Q000503:physiopathology* / Q000517:prevention & control; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D020812:Receptor, trkC / Q000819:agonists* / Q000235:genetics / Q000502:physiology
chemical_list: D020933:Neurotrophin 3; D020812:Receptor, trkC; D048049:Extracellular Signal-Regulated MAP Kinases