NT3-TRKC SIGNALLING DISRUPTS FEAR MEMORY RECONSOLIDATION AND GLUTAMATE RECEPTOR REORGANIZATION

Maladaptive fear memories are a hallmark of anxiety disorders. Upon retrieval, these memories enter a labile state and require reconsolidation – a process dependent on glutamate receptor (GluRs)-mediated synaptic plasticity – offering an opportunity for targeted modification of fear memories. We recently observed that activation of tropomyosin receptor kinase C (TrkC) – the high-affinity receptor for neurotrophin-3 (NT3) – is downregulated in mice hippocampi during fear reconsolidation. In hippocampal synapses, changes in the expression of AMPA and NMDA GluRs (AMPAR and NMDAR) subunits underlie fear reconsolidation and may mediate the effects of NT3-TrkC signaling. Here, we investigate the role of NT3-TrkC in fear memory reconsolidation and the regulation of GluRs. NT3 was administered to mice via ventral hippocampal infusions during the reconsolidation window. In vitro, primary rat hippocampal neurons were stimulated with NT3 to evaluate changes in synaptic-surface expression of AMPAR and NMDAR subunits. NT3 infusion into the ventral hippocampus disrupted fear memory, indicating that downregulation of TrkC activation is required for fear reconsolidation. In vitro, NT3 stimulation induced a re-arrangement of synaptic-surface AMPAR and NMDAR subunits, culminating at six hours post-stimulation in reduced expression of GluA2 subunit of AMPAR and increased expression of GluN2B subunit of NMDAR. These findings suggest that NT3-TrkC signaling regulates GluRs composition, potentially modulating glutamatergic transmission. We hypothesize that TrkC activation disrupts reconsolidation by opposing the synaptic accumulation of GluA2 and the reduction of GluN2B – molecular changes required for memory re-stabilization. These results position TrkC as a promising target for mechanism-based therapeutic interventions in disorders with maladaptive fear memories.