Background: Depression is a prevalent psychiatric disorder linked to excitatory/inhibitory (E/I) neurotransmission imbalance, particularly in the medial prefrontal cortex (mPFC). Propofol, a GABA A receptor agonist, induces rapid mood improvements clinically, yet its antidepressant-like effects and underlying mechanisms remain unclear. Methods: Network pharmacology was used to identify propofol-related targets linked to E/I balance. Male mice exposed to chronic unpredictable mild stress (CUMS) received a single intraperitoneal injection of propofol. Depressive-like behaviors were assessed using the open field, tail suspension, and forced swim tests. GABAergic and glutamatergic signaling in the mPFC was evaluated by Western blotting, immunofluorescence, and fiber photometry calcium imaging. Optogenetic manipulation of mPFC GABAergic interneurons was performed to test their causal involvement. Results: In both male and female mice, compared with the control group, propofol (50 mg·kg⁻¹) significantly reduced CUMS-induced depression-like behaviors, showing optimal efficacy in the OFT, TST, FST and SPT. Propofol increased mPFC GABAergic neuron excitability while suppressing glutamatergic activity. It also restored CUMS-induced reductions in GABAergic (GAD65, GAD67, VGAT, GAT3, GABAAα1, GABAAγ2) and glutamatergic (GluA1, mGlu5, VGLUT1) protein expression. Pharmacologic inhibition of GABA A receptors with the antagonist bicuculline abolished propofol’s antidepressant effects. Optogenetic activation of GABAergic interneurons at 10 Hz enhanced propofol’s antidepressant effects, whereas inhibition attenuated them. Conclusions: Propofol produces rapid antidepressant-like effects through activating the GABA A receptors and restoring the GABA/glutamate balance. These findings suggest that propofol could be a useful tool for investigating the mechanisms of fast-acting antidepressant. Ethical Compliance: The study was approved by the Ethics Committee of Jilin University.
Song et al. (Mon,) studied this question.