Neurotrophic factors help neurons grow, survive, and connect. For decades, scientists thought that too little neurotrophic support caused the loss of synapses and cells seen in psychiatric disorders. Traditional antidepressants raise neurotrophic levels over weeks, matching when they start working. Newer treatments like ketamine and psychedelics work within hours and quickly release neurotrophins into synapses. This has changed how researchers understand neurotrophins and their receptors. This review discusses these new insights into receptor signaling and their clinical importance, building on what is already known about neurotrophic factors in psychiatric disorders and treatments.
Ketamine's antidepressant effects depend on the interplay between two types of neuromodulatory receptors: TrkB and mGluR5. mGluR5 amplifies BDNF-driven signaling through TrkB, enabling synaptic potentiation, while BDNF activation of TrkB drives mGluR5 endocytosis, impairing synaptic depression. Ketamine enhances these interactions by increasing surface and postsynaptic levels of TrkB. An mGluR5 positive allosteric modulator can further boost both modes of cross-talk and enhance ketamine's effects, revealing that receptor-receptor interplay can drive therapeutic action.