Ketamine, a drug used as an anesthetic since the 1970s, has recently gained attention for its rapid antidepressant effects. In preclinical studies, it shows both neurotoxic and neuroprotective properties depending on context. At anesthetic doses during neurodevelopmental windows, it contributes to inflammation, autophagy, apoptosis, and increased reactive oxygen species. At subanesthetic doses, it activates neurotrophic signaling cascades with neuroprotective actions that are not always dependent on its primary receptor. This review summarizes the complex intracellular signaling pathways modulated by ketamine and contrasts its protective and harmful features.
Tiam1, a protein that regulates the structure of synapses, drives hyperactivity in the anterior cingulate cortex (ACC) by reorganizing the actin cytoskeleton and stabilizing NMDA receptors. This maladaptive synaptic plasticity underlies depressive-like behaviors in mouse models of chronic pain. Low-dose ketamine, an NMDA receptor antagonist, produces sustained antidepressant-like effects by blocking Tiam1-mediated changes in ACC neurons. The findings identify Tiam1 as a key molecular factor linking chronic pain to depression and as a target for ketamine's long-lasting effects.