Dose-dependent effects of propofol on GABAergic neurotransmission in the preBotzinger complex and it's consequences on respiratory rhythm.

Abstract

Propofol acts primarily through GABAA receptor-dependent central inhibition, while local inhibitory microcircuits in the preBotzinger complex (preBötC) 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 preBötC circuit function in a complex, dose-related manner. This study aimed to test the hypothesis that propofol modulates preBötC activity via dose-dependent reshaping of local inhibitory microcircuits, rather than producing only monotonic respiratory suppression. Using a mouse model, we combined whole-body plethysmography, optogenetic manipulation of preBötC GABAergic neurons, conditional VGAT knockout, and patch-clamp electrophysiology in acute medullary slices to examine how propofol modulates respiratory rhythm and inhibitory microcircuit activity. 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 preBötC. Light intensity-dependent, sustained optogenetic activation of GABAergic neurons in the preBötC recapitulates the dose-dependent, bidirectional effects of propofol on respiratory activity, while concurrent propofol administration and GABAergic preBötC activation act synergistically to induce respiratory arrest. Selective ablation of GABAergic neurons in the preBötC increased respiratory rate in awake animals, facilitated respiratory recovery after a single propofol bolus, but increased the incidence of apnea during continuous propofol infusion. These results suggest a dose-dependent bidirectional effect of propofol on respiratory drive via the modulation of GABAergic neurons in the preBötzinger Complex.