Dose-dependent Effects of Propofol on GABAergic Neurotransmission in the Pre-Bötzinger Complex and Its Consequences on Respiratory Rhythm.

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.