Time course of inner ear degeneration and deafness in mice lacking the Kir4.1 potassium channel subunit
Introduction
Inwardly rectifying K+ channels regulate the resting membrane potential by (a) contributing much of the resting K+ conductance in many cells and (b) maintaining low extracellular K+ via spatial buffering mechanisms (Hille, 1992, Lagrutta et al., 1996, Isomoto et al., 1997, Reimann and Ashcroft, 1999). The Kir4.1 K+ channel subunit underlies the major K+ conductance in oligodendrocytes in the spinal cord and Müller cells in the retina (Ishii et al., 1997, Kusaka et al., 1999, Kofuji et al., 2000, Neusch et al., 2001). Kir4.1 is also the only inward rectifier known to be expressed in the stria vascularis of the inner ear to date (Hibino et al., 1997, Ando and Takeuchi, 1999). Immunohistochemical studies suggest that Kir4.1 is localized to regions of the stria vascularis near capillaries. An early report presented evidence for specific Kir4.1 expression on marginal cells (Hibino et al., 1997), although later reports show Kir4.1 expression in intermediate cells (Ando and Takeuchi, 1999, Takeuchi et al., 2001). Non-specific blockers of inwardly rectifying K+ channels decreased the endocochlear potential (EP) in vivo (Hibino et al., 1997); furthermore, Kir4.1 expression follows the time course of the developmental pattern of EP generation. These observations have led to the specific hypothesis that Kir4.1 expressed on the intermediate cells helps to generate the EP by spatially buffering K+ at a low level in a distinct intrastrial compartment that is transcellular from the much higher-K+ cochlear endolymph (Takeuchi et al., 2000, Takeuchi et al., 2001). Thus Kir4.1 would help to buffer K+ in a low-K+ extracellular compartment, similar to its function in the Müller cells of the retina and probably elsewhere on glia.
This postulated role implies that animals without Kir4.1 would be deaf. To investigate further the role of the Kir4.1 K+ channel subunit in the ear and in other areas of the CNS, a mouse strain was developed that has a highly specific loss of the Kir4.1 gene product. Impact of this deletion on other areas of the CNS has been published elsewhere (Kofuji et al., 2000, Neusch et al., 2001). Here we report consequences of the gene inactivation for the inner ear at a behavioral and anatomical level. The hypothesis of deafness has been confirmed; furthermore, the Kir4.1 knockout mouse has pronounced anatomical anomalies in the inner ear, showing that Kir4.1 is directly or indirectly required for proper development as well as for acute auditory function. In another recent report, Kir4.1 knockout mice lack EP and have reduced K+ concentration in cochlear endolymph (Marcus et al., 2002).
Section snippets
Materials and methods
Experimentation on animals has been approved by the California Institute of Technology’s Animal Care and Use Committee.
Gross behavioral characterization
Kir4.1−/− mice present a general underdevelopment: they gain less weight than their Kir4.1+/− and WT littermates. Death occurs at 9–21 postnatal days. On a behavioral level, 8–10 days postnatally, mice homozygous for the mutation develop a severe motor impairment with difficulties righting themselves. This behavior could be attributed to a severe defect in spinal cord and brainstem myelination as well as to vacuolation of deep cerebellar nuclei at early stages of development (Neusch et al., 2001
Discussion
Thus far human hereditary deafness syndromes have been largely associated with mutations in outwardly rectifying, voltage-gated (Kv, KvLQT) K+ channels (Vetter et al., 1996, Romey et al., 1997, Schulze-Bahr et al., 1997, Wollnik et al., 1997, Wang et al., 1998, Chen et al., 1999, Talebizadeh et al., 1999, Van Hauwe et al., 1999, Chouabe et al., 2000, Kharkovets et al., 2000). Here we report that disruption of a gene encoding an inwardly rectifying K+ channel can lead to deafness in a mammalian
Acknowledgements
We thank Sami Barghshoon for help with animals. This work was supported by grants from the National Institutes of Health (GM-29836, EY12949), and the Deutsche Forschungsgemeinschaft (NE-767/1-1).
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These authors contributed equally to this study.