FIGURE 1.

Mechanisms of (R)-ketamine antidepressant (partial) (R)-ketamine can activate ERK, thus increasing the expression of NRBP1, BDNF, and p-CREB in primary microglial cells. At the same time, it promotes the release of glutamate into the synaptic cleft, enhances AMPAR flux, activates cellular signaling, and increases the synaptic protein translation of AMPAR subunits and PSD-95, thereby promoting the formation of synapses and dendrites. Additionally, (R)-ketamine can regulate TGF-β signaling in microglial cells, increase the release of BDNF, and subsequently promote binding with the TrkB receptor. Through the MEK-ERK-CREB signaling pathway, it can enhance synaptogenesis and dendritogenesis, thus exhibiting its antidepressant effects. Furthermore, the antidepressant mechanism of (R)-ketamine may also involve the microbiome-gut-brain axis, the brain-spleen axis pathway, and the regulation of miR-132-5p and NFTc4. Abbreviations: AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF: brain-derived neurotrophic factor; CREB: cyclic adenosine monophosphate response element-binding protein; ERK: extracellular signal-related kinase; MEK: mitogen-activated protein kinase; MeCP2: Methyl CpG binding protein 2. NFATc4: nuclear factor of activated T cells 4; PSD-95: postsynaptic density protein 95; TGF-β: transforming growth factor β; TrkB: tropomyosin receptor kinase B.