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 (CNS). It serves as the primary water channel in the neuropil and plays roles in physiological functions, including regulating water homeostasis by adjusting cell volume and modulating neuronal activity. Different isoforms of AQP4 are expressed in glial-like cells known as sustentacular cells (SUSs) of the olfactory epithelium (OE). Notably, mice lacking all AQP4 isoforms exhibit impaired olfactory abilities. Therefore, we aim to uncover the physiological role of AQP4 isoforms, particularly the AQP4ex isoforms (AQP4M1ex, AQP4M23ex) and the orthogonal array of particles (OAPs)-forming isoform (AQP4M23) in the OE. We investigated the impact of AQP4 isoforms on the OE, observing a reduced number of mature olfactory sensory neurons (OSNs), SUSs, and globose basal cells (GBCs) in mice lacking AQP4ex (AQP4ex-KO) or OAPs (OAP-null). This suggests that AQP4 isoforms are involved in maintaining an optimal microenvironment in the OE, preserving cell density. Next, we explored the role of AQP4 in modulating odorant-evoked responses through electro-olfactogram recordings, where we found reduced odorant responses in mice lacking AQP4 isoforms. Assessments of olfactory ability revealed deficits in odor-guided food-seeking behavior in both AQP4ex-KO and OAP-null mice. Furthermore, AQP4ex-KO mice exhibited a diminished 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, influencing odorant-evoked responses and cell density in the OE, with AQP4ex emerging as a key regulator despite its low abundance.