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Background: The medial prefrontal cortex plays a crucial role in regulating consciousness. However, the specific functions of its excitatory and inhibitory networks during anesthesia remain uncertain. Here we explored the hypothesis that somatostatin interneurons in the medial prefrontal cortex enhance the effects of sevoflurane anesthesia by increasing GABA transmission to pyramidal neurons., Methods: EEG was utilized to reflect the depth of anesthesia. Immunostaining and fiber photometry were employed to assess neuronal activities and GABA delivery. The regulation of neuronal activity was achieved by chemogenetics and optogenetics., Results: The expression of c-Fos was increased in somatostatin neurons of the medial prefrontal cortex during sevoflurane anesthesia (air versus sevoflurane: 26.4 ± 6.5 % versus 48 ± 6.2 %, P=0.0007, n=5 mice). Chemogenetic inhibition or activation of somatostatin neurons in the medial prefrontal cortex reduced (from 84 ± 24 s to 51 ± 18 s, P=0.008, n=7 mice) or prolonged (from 97 ± 31 s to 140 ± 30 s, P=0.006, n=7 mice) the sevoflurane anesthesia recovery time. Increased GABA input to pyramidal neurons in the medial prefrontal cortex precedes sevoflurane-induced loss of consciousness (ΔF/F: from 0.46 ± 0.57 % to 2.25 ± 1.42 %, P=0.031, n=10 mice). Activation of somatostatin neurons in the medial prefrontal cortex, leading to a significant reduction in calcium signals within local pyramidal neurons (ΔF/F: from -0.14 ± 0.52 % to -10.08 ± 4.44 %, P=0.002, n=10 mice), and GABA input on pyramidal neurons increased (ΔF/F: from -0.001 ± 0.001 % to 0.28 ± 0.03 %, P=0.002, n=7 mice) in a time-locked manner. Chemogenetic inhibition of pyramidal neurons prolonged the recovery from sevoflurane anesthesia in mice (from 101 ± 46 s to 136 ± 54 s, P=0.017, n=19 mice)., Conclusions: Cortical somatostatin neurons may inhibit local pyramidal neurons by enhancing GABA transmission, which increases the effectiveness of sevoflurane anesthesia., Competing Interests: Conflicts of Interest: The authors declare no competing interests., (Copyright © 2025 American Society of Anesthesiologists. All Rights Reserved.)