Abstract
Homozygous deafwaddler mice (dfw/dfw) have a mutation in the gene encoding plasma membrane Ca2+ATPase isoform 2 (Pmca2). They walk with a hesitant and wobbly gait, display head bobbing and are deaf. Light microscopy and transmission electron microscopy were used to evaluate the nature and relationship of morphological changes in the cochlea, spiral ganglion cells and spherical cells of the cochlear nucleus in homozygous and heterozygous mice of different ages and controls. Ultrastructural findings showed that in 7 week old homozygous (dfw) mice, inner hair cells and their afferent terminals were present although outer hair cells appeared apoptotic. Stereocilia were absent from the second and third rows of outer hair cells. Ganglion cells were also present although abnormal in appearance. In older homozygous mutants there was a loss of hair cells and spiral ganglion cells. Remaining ganglion cells in this group contained very few cytoplasmic organelles apart from a few hypertrophied mitochondria. In the anteroventral cochlear nucleus, spherical cell soma size was smaller in all homozygous (dfw) mutants than in heterozygous mice and controls. The ultrastructural appearance of the end bulbs of Held in homozygous mutants was abnormal compared with controls, and in the younger group were seen to be swollen, with less distinct synaptic densities and containing large numbers of small synaptic vesicles arranged in clumps. In the older group these synapses were distorted and contained hypertrophied mitochondria and no synaptic densities could be seen, suggesting that these synapses may be non-functional. This study has shown that in homozygous (dfw) mice structural abnormalities occurred not only in cochlear hair cells but also in the spiral ganglion neurones and spherical cells in the cochlear nucleus. It seems likely that these changes are the result of the Pmca2 mutation and the subsequent accumulation of toxic levels of calcium that may lead to alterations in their functional integrity.
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References
Choi., D. W. (1992) Excitotoxic cell death. (Review). Journal of Neurobiology 23, 1261–1276.
Choi, D. W. & Hartley, D. M. (1993) Calcium and glutamate-induced cortical neuronal death. In Molecular and Cellular Approaches to the Treatment of Neurological Disease (edited by Waxman, S. G.) pp. 11–50. New York: Raven Press.
Coleman, J. R. & O'Connor, P. (1979) Effects of monaural and binaural sound deprivation on cell development in the anterovenral cochlear nucleus of rats. Experimental Neurology 64, 553–566.
Cowan, W. M. (1970) Anterograde and retrograde transneuronal degeneration in the central and peripheral nervous system. In Contemporary Research Methods in Neuroanatomy (edited by Nauta, W. J. H. & Ebbesson, S. O. E.) pp. 217–249. Berlin: Springer.
Denk, W., Holt, J. R., Shepherd, G. M. G. & Corey, D. P (1995) Calcium imaging of single stereocilia in hair cells: Localisation of transduction channels at both ends of tip links. Neuron 15, 1311–1321.
Dodson, H. C. (1997) Loss and survival of spiral ganglion neurones in the guinea pig after intracochlear perfusion with aminoglycosides. Journal of Neurocytology 26, 541–544.
Dodson, H. C. & Charalabapoulou, M. (2000) Changes in the anteroventral cochlear nucleus of the deafwaddler mouse. British Journal of Audiology 34, 86–87.
Dodson, H. C. & Mohuiddin, A. (2000) Response of spiral ganglion neurones to cochlear hair cell destruction in the guinea pig. Journal of Neurocytology 29, 525–537.
Furata, H., Luo, L., Hepler, K. & Ryan, A. F. (1998) Evidence for differential regulation of calcium by outer versus inner hair cells: Plasma membrane Ca-ATPase gene expression. Hearing Research 123, 10–26.
Huchton, D., M., Pongstaporn, T., Niparki, J. K. & Ryugo, D. K. (1997) Ultrastructural changes in primary endings of deaf white cats. Otolaryngology 116, 286–293.
Kater, S. B., Mattson, M. P., Cohan, C. & Connor, J. (1988) Calcium regulation of the neuronal growth cone. Trends in Neuroscience 11, 315–321.
Koike, T., Martin, D. P. & Johnson, E. M. J. (1989) Role of Ca2+ channels in the ability of membrane depolarisation to prevent neuronal death induced by trophic-factor deprivation: Evidence that levels of internal Ca2+ determine nerve growth factor dependence of sympathetic ganglion cells. Proceedings of the National Academy of Science of the USA 86, 6421–6425.
Konrad-Martin, D., Norton, S. J., Mascher, K. E. & Tempel, B. (2001) Effects of PMCA2 mutation on DPOAE amplitudes and latencies in deafwaddler mice. Hearing Research 151, 205–220.
Kozel, P. J., Friedman, R. A., Erway, L. C., Yamoah, E. N., Liu, L. H., Riddle, T., Duffy, J. J., Doetsman, T., Miller, M. L., Cardell, E. L. & Shull, G. E. (1998) Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+?ATPase isoform 2. Journal of Biological Chemistry 273, 18693–18696.
Kruman, I. I. & Mattson, M. P. (1999) Pivotal role of mitochondrial calcium uptake in neural cell apotosis and necrosis. Journal of Neurochemistry 72, 529–540.
Lachica, E. A., Zirpel, L. & Rubel, E. W. (1996) Intracellular mechanisms involved in the afferent regulation of neurones in the avian cochlear nucleus. In Auditory System Plasticity and Regeneration (edited by Salvi, R. J., Henderson, D., Fiorino, F. & Colletti, V.) pp. 333–353. Thieme Medcial Publishers.
Larmet, E. A., Dolphin, A. C. & Davies, A. M. (1992) Intracellular calcium regulates the survival of early sensory neurones before they become dependent on neurotrophic factors. Neuron 9, 563–574.
Moore, D. R. (1985a) Postnatal development of the mammalian central auditory system and the neural consequences of the auditory deprivation. Acta Otolaryngology (Stockh) Suppl. 421, 19–30.
Moore, D. R. (1985b) Critical periods for binaural interaction and spatial representation. Acta Otolaryngology (Stockh) Suppl. 429, 51–55.
Moore, D. R., Rogers, N. J. & O'Leary, S. (1998) Loss of cochlear nucleus neurons following aminoglycoside antibiotics or cochlear removal. Annals of Otology Rhinology and Laryngology 107, 337–343.
Noben-Trauth, K., Zheng, Q. Y., Johnson, K. R. & Nishina, P. M. (1997) (mdfw): A deafness susceptibility locus that interacts with deaf waddler (dfw). Genomics 44, 266–272.
Norton, S. J., Tempel, B. L., Steel, K. P. & Rubel, E. W. (1996) Physiological and anatomical status of the deafwaddler (dfw) mutant mouse cochlea. “Abstracts of the 20th Annual Midwinter Research Meeting of the Association for Research in Otolaryngology” (edited by Popelar, G. R.) pp. 82, St. Petersburg Beach Florida.
Otte, J., Schucknecht, H. F. & Kerr, A. G. (1978) Ganglion cell population in normal and pathological human cochlea: Implications for cochlear implantation. Laryngoscope 88, 1231–1246.
Paschen, W. (2000) Role of calcium in neuronal injury: Which subcellular compartment is involved? Brain Research Bulletin 53, 409–413.
Pasic, T. E. & Rubel, E. W. (1989) Rapid changes in cochlear nucleus cell size following blockade of auditory nerve electrical activity in gerbils. Journal of Comparative Neurology 283, 474–480.
Pujol, R., Cunningham, B. L., Tempel, B. L. & Rubel, E. W. (1997) Abnormal morphological development in the deafwaddler (dfw) mouse mutant cochlea: A TEM study. In “Abstracts of the Twentieth Annual Midwinter Research Meeting of the Association for Research in Otolaryngology” (edited by Popelar, G. R.) St. Petersburg Beach, Florida (Abstract, 442).
Ryugo, D. K., Pongstaporn, T., Huchton, D. M. & Niparko, J. K. (1997) Ultrastructural Analysis of Primary Endings in the Deaf White Cats: Morphological alterations in Endbulbs of Held. Journal of Comparative Neurology 385, 230–244.
Schwartz, I. R. & Higa, J. F. (1982) Correlated studies of the ear and brainstem in the deaf white cat: Changes in the spiral ganglion and the medial superior olivary nucleus. Acta Otolaryngology 93, 9–18.
Steel, K. P. (1995) Inherited hearing defects in mice. Annual Review of Genetics 29, 675–701.
Steel. K. P. & Kros, C. J. (2001) A genetic approach to understanding auditory function. Nature Genetics 27, 142–149.
Street, V. A., McKee-Johnson, J. W., Fonseca, R. C., Tempel B. L. & Noben-Trauth, K. (1998) Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice. Nature Genetics 19, 390–394.
Street, V. A., Robinson, L. C., Erford, S. K. & Tempel, B. L. (1995) Molecular genetic analysis of distal mouse chromosome 6 defines gene order and positions of the deafwaddler and opisthotonos mutations. Genomics 29, 123–130.
Warshawsky, H. & Moore, G. (1967) A technique for the fixation and decalcification of rat incisors for electron micrsoscopy. Journal of Histochemistry and Cytochemistry 15, 542–549.
Yamoah, N. E., Lumpkin, E. A., Dumont, R. A., Smith, P. J. S., Hudspeth, A. J. & Gillespie, P. G. (1998) Plasma membrane Ca-ATPase extrudes Ca from hair cell stereocilia. Journal Neuroscience 18, 610–624.
Ylikoski, J. (1974) Correlation between pure tone audiogram and cochlear pathology in guinea pigs intoxicated with ototoxic antibiotics. Acta Otolaryngology 326, 42–62.
Ylikosi, J., Wersall, J. & Bjorkroth, B. (1974) Degeneration of neural elements in the cochlea of the guinea pig after damage of the organ of Corti by ototoxic antibiotics. Acta Otolaryngology 326, 23–41.
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Dodson, H., Charalabapoulou, M. PMCA2 mutation causes structural changes in the auditory system in deafwaddler mice. J Neurocytol 30, 281–292 (2001). https://doi.org/10.1023/A:1014489527996
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DOI: https://doi.org/10.1023/A:1014489527996