Neuronal plasticity is a fundamental process in neuronal development and recovery from brain disorders. The Trophin lab focuses on the role of neurotrophic factors, particularly Brain-Derived Neurotrophic Factor (BDNF) and its receptor TRKB, in plasticity of the adult brain and in the mechanisms of action of drugs used for the treatment of brain disorders. Our particular focus has been on the mechanism of antidepressant drug action. We have discovered that antidepressant drugs, including typical and fast-acting antidepressants, directly bind to TRKB receptors and allosterically promote BDNF signaling. TRKB signaling in turn induces a critical period-like plasticity that leads to beneficial rewiring of neuronal networks when antidepressant-induced plasticity is combined with training that guides plastic networks.
The Trophin lab is currently investigating details of the mechanisms how antidepressants and other compounds activate BDNF signaling using advanced microscopy (both in vitro in cultured neurons and in vivo in mouse brain), biochemistry, molecular modeling and structural studies. To reveal how TRKB signaling promotes plasticity of neuronal networks, we are using optically activated TRKB (optoTRKB), in vivo imaging, single cell transcriptomics and electrophysiology. We are also pursuing behavioral models where neuronal activity is stimulated to guide drug-induced plasticity.
Our work has revealed a completely new mechanism of antidepressant drug action which links molecular drug effects directly to brain plasticity, suggesting new strategies for more effective treatment. Mechanisms of neuronal plasticity are also highly pertinent to the recovery from other brain disorders, such as neurodegeneration and trauma.