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. 2008 Sep;22(9):3216-23.
doi: 10.1096/fj.07-104836. Epub 2008 May 29.

Impaired olfaction in mice lacking aquaporin-4 water channels

Daniel C Lu  1 , Hua Zhang, Zsolt Zador, A S Verkman
Affiliations

Impaired olfaction in mice lacking aquaporin-4 water channels

Daniel C Lu et al. FASEB J. 2008 Sep.

Abstract

Aquaporin-4 (AQP4) is a water-selective transport protein expressed in glial cells throughout the central nervous system. AQP4 deletion in mice produces alterations in several neuroexcitation phenomena, including hearing, vision, epilepsy, and cortical spreading depression. Here, we report defective olfaction and electroolfactogram responses in AQP4-null mice. Immunofluorescence indicated strong AQP4 expression in supportive cells of the nasal olfactory epithelium. The olfactory epithelium in AQP4-null mice had identical appearance, but did not express AQP4, and had approximately 12-fold reduced osmotic water permeability. Behavioral analysis showed greatly impaired olfaction in AQP4-null mice, with latency times of 17 +/- 0.7 vs. 55 +/- 5 s in wild-type vs. AQP4-null mice in a buried food pellet test, which was confirmed using an olfactory maze test. Electroolfactogram voltage responses to multiple odorants were reduced in AQP4-null mice, with maximal responses to triethylamine of 0.80 +/- 0.07 vs. 0.28 +/- 0.03 mV. Similar olfaction and electroolfactogram defects were found in outbred (CD1) and inbred (C57/bl6) mouse genetic backgrounds. Our results establish AQP4 as a novel determinant of olfaction, the deficiency of which probably impairs extracellular space K(+) buffering in the olfactory epithelium.

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Figures

Figure 1.
Figure 1.
Impaired olfaction in AQP4-null mice shown by behavioral testing. Olfactory performance was tested in buried food pellet and olfactory maze tests as described in Materials and Methods. A) Buried food pellet test. The latency for mice (CD1 and C57/bl6 genetic backgrounds) to recover a buried food pellet was recorded on each of 3 consecutive testing days (mean±se, 10 mice/group; *P<0.001, paired t test). Latency times not significantly different in control visible pellet test (P=0.16 for CD1, P=0.31 for C57/bl6; control data shown from last testing day). B) Olfactory maze test. The latency for mice (CD1 and C57bl6 genetic backgrounds) to recover a hidden food pellet was recorded (mean±se, 10 mice per group; *P<0.001, paired t test). Latency times not significantly different in control visible pellet test (P=0.21 for CD1; P=0.28 for C57/bl6). Inset: schematic of maze.
Figure 2.
Figure 2.
Reduced osmotic water permeability in AQP4-deficient olfactory epithelium. A) Left panel: diagram of the olfactory epithelium. Inset: calcein-stained OE. Right panel: schematic of perfusion chamber with freshly isolated olfactory epithelium immobilized on the nylon mesh and all surfaces exposed to solutions. Inset: perfusate exchange time as measured by perfusion with PBS followed by fluorescein-containing PBS. B) Left panel: representative calcein fluorescence recordings in response to hypoosmolar challenge. Solution osmolarities changed from 300 to 150 mosmol at upward deflections and 150 to 300 mosmol at downward deflections. Right panel: reciprocal exponential time constants for osmotic equilibration (τ−1, in s−1) in olfactory epithelium from wild-type and AQP4-null mice. Individual measurements (•) and mean ± se (○). *P < 0.001.
Figure 3.
Figure 3.
Impaired electrophysiological olfactory responses in AQP4-null mice. EOGs were recorded in response to brief exposure of the olfactory epithelia to vapor-phase odorants. A) Representative EOGs of wild-type and AQP4-null mice (CD1 genetic background) to odorants of different chemical classes. B) Representative EOGs in response to exposure to air (20 cc) or air saturated with trimethylamine (20, 10, 5, and 1 cc). C) Summary of maximum voltage responses to indicated doses of triethylamine, from experiments as in B, for mice in CD1 and C57/Bl6 genetic backgrounds (mean±se, 10 mice/group, *P<0.005 by paired t test).
Figure 4.
Figure 4.
AQP4 expression in olfactory epithelium. A) OMP (ORN marker, green) and AQP4 (red) immunofluorescence of OE from wild-type and AQP4-null mouse (apical surface facing down). B) Immunofluorescence of dissociated cells. Left panels: low-magnification images showing green-stained ORNs (white arrows) and red-stained AQP4-expressing cells (gray arrows). Right panels: high-magnification images showing examples of individual cells stained green or red only (top) and one example of a cell stained green and red (bottom). Scale bars = 10 μm (A); 50 μm (B).
See this image and copyright information in PMC

References

    1. Manley G T, Fujimura M, Ma T, Noshita N, Filiz F, Bollen A W, Chan P, Verkman A S. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6:159–163. - PubMed
    1. Papadopoulos M C, Saadoun S, Binder D K, Manley G T, Krishna S, Verkman A S. Molecular mechanisms of brain tumor edema. Neuroscience. 2004;129:1011–1020. - PubMed
    1. Saadoun S, Papadopoulos M C, Watanabe H, Yan D, Manley G T, Verkman A S. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. J Cell Sci. 2005;118:5691–5698. - PubMed
    1. Auguste K I, Jin S, Uchida K, Yan D, Manley G T, Papadopoulos M C, Verkman A S. Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury. FASEB J. 2007;21:108–116. - PubMed
    1. Li J, Verkman A S. Impaired hearing in mice lacking aquaporin-4 water channels. J Biol Chem. 2001;276:31233–31237. - PubMed

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