In the scope of the research project 85/18 - Role of NT3/TrkC in the regulation of fear, supported by the BIAL Foundation, Mónica Santos and colleagues, using a behavioural model of fear extinction, assessed mice that successfully extinguish fear and those that fail. Inter-individual differences in the ability to extinguish fear have a dual outcome: first on setting the vulnerability to develop anxiety and fear-related disorders, and second on determining the effectiveness of exposure therapy towards patients in this group of disorders. Indeed, fear extinction mechanisms that support exposure therapy principles are often impaired in patients with fear-related disorders. The formation of fear memories and their extinction is dependent on synaptic plasticity events occurring at amygdalar fear and extinction microcircuits. Using the aforesaid model, the team identified a key role for the NT3-TrkC system in fear extinction, through modulation of amygdalar NMDAR composition and synaptic plasticity. This study validates the TrkC pathway as a potential therapeutic target for individuals with fear-related disorders and reveals that combining exposure therapies with drugs that enhance synaptic plasticity may represent a more effective and lasting way of treating anxiety disorders. To know more read the paper The amygdala NT3-TrkC pathway underlies inter-individual differences in fear extinction and related synaptic plasticity published in the journal Molecular Psychiatry.
ABSTRACT
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.
