Impaired Hearing in Mice Lacking Aquaporin-4 Water Channels

Abstract

A role for aquaporins (AQPs) in hearing has been suggested from the specific expression of aquaporins in inner ear and the need for precise volume regulation in epithelial cells involved in acoustic signal transduction. Using mice deficient in selected aquaporins as controls, we localized AQP1 in fibrocytes in the spiral ligament and AQP4 in supporting epithelial cells (Hensen's, Claudius, and inner sulcus cells) in the organ of Corti. To determine whether aquaporins play a role in hearing, auditory brain stem response (ABR) thresholds were compared in wild-type mice and transgenic null mice lacking (individually) AQP1, AQP3, AQP4, and AQP5. In 4 -5-week-old mice in a CD1 genetic background, ABR thresholds in response to a click stimulus were remarkably increased by >12 db in AQP4 null mice compared with wild-type mice (p < 0.001), whereas ABR thresholds were not affected by AQP1, AQP3, or AQP5 deletion. In a C57/bl6 background, nearly all AQP4 null mice were deaf, whereas ABRs could be elicited in wildtype controls. ABRs in AQP4 null CD1 mice measured in response to tone bursts (4 -20 kHz) indicated a frequency-independent hearing deficit. Light microscopy showed no differences in cochlear morphology of wildtype versus AQP4 null mice. These results provide the first direct evidence that an aquaporin water channel plays a role in hearing. AQP4 may facilitate rapid osmotic equilibration in epithelial cells in the organ of Corti, which are subject to large K ؉ fluxes during mechano-electric signal transduction.The aquaporins (AQPs) 1 are a family of small integral membrane proteins that function as water transporters. Phenotype analysis of mice lacking aquaporins has indicated that they play a physiological role in the kidney, central nervous system, gastrointestinal system, and exocrine glands (reviewed in Ref. 1). Mice lacking AQP1, AQP2, or AQP3 manifest nephrogenic diabetes insipidus with defective urinary concentrating ability (2-4), mice lacking AQP4 have altered brain water balance in response to injury (5), and mice lacking AQP5 have defective saliva secretion (6). In humans, mutations in AQP2 cause the autosomal form of hereditary nephrogenic diabetes insipidus (7). Phenotype studies have also shown the tissue-specific expression of an aquaporin does not prove its physiological importance. For example, mice lacking AQP4 in gastric parietal cells and skeletal muscle have unimpaired stomach acid secretion (8) and skeletal muscle function (9). The data from aquaporin null mice suggest that aquaporins are functionally important in tissues carrying out rapid near isosmolar fluid transport or passive water transport driven by osmotic gradients (1).Several aquaporins have been localized in the mammalian inner ear and have been proposed to play a role in hearing. Reverse transcriptase polymerase chain reaction analysis of dissected rat inner ear showed diffuse AQP1 transcript expression, specific expression of AQP2, AQP3, and AQP4 in the endolymphatic sac, and expression of AQP5 in the organ of Corti and Reissn...

Functions of aquaporins in the eye

“…AQP4 is expressed in supportive cells adjacent to electrically excitable cells, as in Müller vs. bipolar cells in retina, glia vs. neurons in brain, and hair vs. supportive cells in the inner ear. Electrophysiological measurements have demonstrated impaired auditory and visual signal tranduction in AQP4 null mice, seen as increased auditory brainstem response thresholds (Li and Verkman, 2001) and reduced electroretinogram potentials (Li et al, 2002). In brain, seizure threshold is reduced and seizure duration prolonged in AQP4 deficiency (Binder et al, 2004a).…”

“…The visual deficit associated with AQP4 deficiency adds to the auditory and olfactory sensory deficits described in AQP4 null mice (Li and Verkman, 2001;Lu et al, 2008), and to the related neural signaling phenotype of altered seizure susceptibility and severity (Binder et al, 2004a;. How AQP4-expressing Müller cells are functionally coupled to bipolar cells remains a subject of ongoing investigation.…”

Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

“…Fear conditioning task was performed to examine the behavioral consequences of the depletion of AQP4 at the intact animal level. Considering that the hearing of AQP4 KO mice is impaired (Li and Verkman, 2001), we used light but not tone as CS in fear conditioning test. In Pavlovian fear conditioning, memory acquisition refers to the process mediating the initial learning of the CS-US association during the training of fear conditioning, whereas memory consolidation refers to the process converting short-term memories into stable long-term memories (Abel and Lattal, 2001;Makkar et al, 2010).…”

Binding Affinity and Specificity of Neuromyelitis Optica Autoantibodies to Aquaporin-4 M1/M23 Isoforms and Orthogonal Arrays

“…The target of the NMO autoantibody, AQP4, is involved in water balance in brain (8,9) and spinal cord (10), sensory signal transduction (11,12) and neuroexcitatory phenomena including seizure activity (13) and cortical spreading depression (14), and astrocyte migration and glial scarring (15,16). AQP4 is expressed in astrocytes as two major isoforms: a long (M1) isoform with translation initiation at Met-1, and a shorter (M23) isoform with translation initiation at Met-23 (17)(18)(19)(20).…”