Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice

Abstract

The Olfr78 gene encodes a G-protein coupled receptor that is expressed in olfactory sensory neurons, where it functions as a conventional odorant receptor, and also in several ectopic sites, where its function is not well understood. Olfr78 is one of the most highly expressed mRNA species in glomus cells of the carotid body (CB). These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in Olfr78 knockout mice. In another study, Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. These organismal phenotypes could result from pleiotropic effects of the constitutive Olfr78 knockout mutations in the various CB cell types and/or various organs where this gene is expressed. Therefore, to further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for the phenotypic specification of mature glomus cells.