The Aquaporin-4 expression and localization in the olfactory epithelium modulate the odorant-evoked responses and olfactory driven behavior

Aquaporin-4 (AQP4) is a water-selective channel expressed in glial cells throughout the central nervous system. It serves as the main water channel in the neuropil, and is involved in various physiological functions, ranging from regulating water homeostasis by adjusting cell volume to modulating neuronal activity. Different isoforms of AQP4 are expressed in glial-like cells known as sustentacular cells (SUSs) of the olfactory epithelium (OE). Interestingly, mice lacking all AQP4 isoforms exhibit impaired olfactory abilities. Hence, we aim to uncover the physiological role of two AQP4 isoforms, the perivascular AQP4ex isoform and the Orthogonal Array of Particle (OAP)-forming isoform (AQP4M23) in the OE. Primarily, we investigated the impact of AQP4 isoforms on OE protein expression, finding reduced levels of mature olfactory sensory neurons (OSNs) in mice lacking AQP4ex (AQP4ex-KO) or OAPs (OAP-null). Moreover, the reduced number of OSNs, SUSs, and globose basal cells (GBCs) suggests that AQP4 isoforms are involved in maintaining an optimal microenvironment in the OE, preserving the overall cell density. Then, we explored the role of AQP4 in modulating odorant-evoked responses through electro-olfactogram recordings, finding reduced odorant responses in mice lacking AQP4 isoforms. Olfactory ability assessments revealed deficits in odor-guided food-seeking test in AQP4ex-KO and OAP-null mice. Furthermore, AQP4ex-KO mice showed a reduced ability to discriminate between different odorants, while OAP-null mice were unable to recognize them as distinct. Overall, our data highlight the role of AQP4 isoforms in modulating neuronal homeostasis, affecting odorant-evoked responses and cell density in the OE. These results shed light on SUSs involvement in mediating these processes and establish a foundation for further understanding their role in controlling OE physiology.