Ketamine, a drug that blocks NMDA receptors, rapidly activates the mTOR pathway in the prefrontal cortex of rats, increasing synaptic signaling proteins and the number and function of new spine synapses. Blocking mTOR signaling prevented ketamine from inducing synaptogenesis and behavioral antidepressant-like responses in depression models. These effects reverse the synaptic deficits caused by stress and may explain ketamine's fast antidepressant action in treatment-resistant depressed patients, which contrasts with the weeks or months needed for standard medications.
Stress and antidepressant treatments have opposing effects on neurotrophic factors like brain-derived neurotrophic factor in brain regions such as the hippocampus and prefrontal cortex (PFC). Stress reduces these factors, leading to decreased neurogenesis, dendrite length, and spine density, which may contribute to the reduced brain volume seen in depressed patients. Antidepressant treatments can block or reverse this atrophy. A novel rapid-acting antidepressant, ketamine, an NMDA receptor antagonist, rapidly induces synaptogenesis and spine formation in the PFC by stimulating the mammalian target of the rapamycin signaling pathway and increasing synaptic protein synthesis. These effects reverse chronic stress-induced PFC neuron atrophy and correspond to rapid behavioral actions in depression models, identifying new cellular targets for rapid antidepressant actions without ketamine's side effects.