Anesthesiology · 2026
Dose-dependent Effects of Propofol on GABAergic Neurotransmission in the Pre-Bötzinger Complex and Its Consequences on Respiratory Rhythm.
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Jiang Junli, Ai Shiqing, Chen Ya, You Zhiyuan, Shen Feng, Yuan Chengdong, Cheng Qiuping, Tang Chunchun, Zhou Liang, Yu Shouyang, Zhang Lin, Wang Haiying, Shen Wei L, Yu Weifeng, Yu Tian
Аннотация
BACKGROUND: Propofol acts primarily through γ-aminobutyric acid type A receptor-dependent central inhibition, while local inhibitory microcircuits in the pre-Bötzinger complex (pre-BötC) exert bidirectional control over respiratory rhythm. Although propofol is widely recognized as a simple respiratory depressant, it remains unclear whether propofol mimics endogenous inhibitory signaling to disrupt pre-BötC circuit function in a complex, dose-related manner. This study aimed to test the hypothesis that propofol modulates pre-BötC activity via dose-dependent reshaping of local inhibitory microcircuits rather than producing only monotonic respiratory suppression.
METHODS: Using a mouse model, the authors combined whole-body plethysmography, optogenetic manipulation of pre-BötC γ-aminobutyric acid-mediated (GABAergic) neurons, conditional VGAT knockout, and patch clamp electrophysiology in acute medullary slices to examine how propofol modulates respiratory rhythm and inhibitory microcircuit activity.
RESULTS: Propofol induced dose-dependent, bidirectional respiratory effects ranging from mild excitation to marked suppression with increasing anesthetic depth. These changes correlated with concordant, dose-dependent excitatory and inhibitory effects of the drug on glutamatergic neurons in the pre-BötC. Light intensity-dependent, sustained optogenetic activation of GABAergic neurons in the pre-BötC recapitulates the dose-dependent, bidirectional effects of propofol on respiratory activity, while concurrent propofol administration and GABAergic pre-BötC activation act synergistically to induce respiratory arrest. Selective ablation of GABAergic neurons in the pre-BötC increased respiratory rate in awake animals, facilitated respiratory recovery after a single propofol bolus but increased the incidence of apnea during continuous propofol infusion.
CONCLUSIONS: These results suggest a dose-dependent bidirectional effect of propofol on respiratory drive via the modulation of GABAergic neurons in the pre-Bötzinger complex.
METHODS: Using a mouse model, the authors combined whole-body plethysmography, optogenetic manipulation of pre-BötC γ-aminobutyric acid-mediated (GABAergic) neurons, conditional VGAT knockout, and patch clamp electrophysiology in acute medullary slices to examine how propofol modulates respiratory rhythm and inhibitory microcircuit activity.
RESULTS: Propofol induced dose-dependent, bidirectional respiratory effects ranging from mild excitation to marked suppression with increasing anesthetic depth. These changes correlated with concordant, dose-dependent excitatory and inhibitory effects of the drug on glutamatergic neurons in the pre-BötC. Light intensity-dependent, sustained optogenetic activation of GABAergic neurons in the pre-BötC recapitulates the dose-dependent, bidirectional effects of propofol on respiratory activity, while concurrent propofol administration and GABAergic pre-BötC activation act synergistically to induce respiratory arrest. Selective ablation of GABAergic neurons in the pre-BötC increased respiratory rate in awake animals, facilitated respiratory recovery after a single propofol bolus but increased the incidence of apnea during continuous propofol infusion.
CONCLUSIONS: These results suggest a dose-dependent bidirectional effect of propofol on respiratory drive via the modulation of GABAergic neurons in the pre-Bötzinger complex.