M1/M3 and M2/M4 muscarinic receptor double-knockout mice present distinct respiratory phenotypes

We investigated the role of muscarinic acetylcholine receptors in the control of breathing. Baseline breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O2) and hypercapnia (3% and 5% CO2), measured by whole-body plethysmography in partially restrained animals, were compared in mice lacking either M1 and M3 or M2 and M4 muscarinic receptors, and in wild-type matched controls. M1/3R double-knockout mice showed at rest an elevated ventilation (V˙E) due to a large (57%) increase in tidal volume (VT). Chemosensory ventilatory responses were unaltered. M2/4R double-knockout mice were agitated and showed elevated V˙E and breathing frequency (fR) at rest when partially restrained, but unaltered V˙E and low fR when recorded unrestrained. Chemosensory ventilatory responses were unaltered. The results suggest that M1 and M3 receptors are involved in the control of tidal volume, while M2 and M4 receptors may be involved in the control of breathing frequency at rest and response to stress.