Rethinking the role of TRKB in the action of antidepressants and psychedelics.

Antidepressant drugs, including slow-acting types, fast-acting ketamine, and psychedelics, all promote neuronal plasticity through activation of BDNF signaling via its receptor TRKB, though each drug targets different cells. The authors propose that some antidepressants may directly bind to TRKB and allosterically enhance BDNF signaling. Activating TRKB in parvalbumin-containing interneurons disinhibits cortical networks and reopens a juvenile-like window of plasticity. This rewiring of faulty neural circuits, combined with environmental input, may explain clinical antidepressant effects. This hypothesis could guide development of new treatments.

Study at a glance

Abstract

Antidepressant drugs promote neuronal plasticity, and activation of brain-derived neurotrophic factor (BDNF) signaling through its receptor neuronal receptor tyrosine kinase 2 (NTRK2 or TRKB) is among the critical steps in this process. These mechanisms are shared by typical slow-acting antidepressants, fast-acting ketamine, and psychedelic compounds, although the cellular targets of each drug differ. In this opinion article, we propose that some of these antidepressants may directly bind to TRKB and allosterically potentiate BDNF signaling, among other possible effects. TRKB activation in parvalbumin-containing interneurons disinhibits cortical networks and reactivates a juvenile-like plasticity window. Subsequent rewiring of aberrant networks, coupled with environmental stimuli, may underlie its clinical antidepressant effects. The end-to-end hypothesis proposed may stimulate the search for new treatment strategies.