Restoration of Brain Stem Auditory-Evoked Potentials by Gene Transfer in Shiverer Mice

Abstract

We studied the shiverer mouse as a model for correcting hearing disorders resulting from genetic abnormalities of the central nervous system (CNS). Shiverer mice are homozygous for an autosomal recessive mutation (deletion) in the gene for myelin basic protein (MBP), a major protein component of the myelin sheath in the CNS. Under electron microscopic observation of the cochlear nerve, the CNS portion in shiverer mice showed hypomyelination, but the peripheral portion, including spiral ganglion cells, was normal. We produced MBP-transgenic mice by microinjection of an MBP cosmid clone into the pronucleus of fertilized eggs from shiverer mice. The transgenic mice were found to recover MBP levels up to 25% of normal. A greater number of axons in the transgenic mice were myelinated than in the shiverer mice, but the myelin sheath was not as thick as in normal controls. Every interpeak latency of brain stem auditory-evoked potentials was prolonged in the shiverer mice and improved in the transgenic mice. This study provides an example of gene therapy for hearing disorders caused by a CNS abnormality. We discuss some strategies for researching genetic hearing impairment or deafness in both animals and humans.

Keywords

auditory-evoked potential cochlear nerve electron microscopy myelin basic protein myelin sheath shiverer mice transgenic mice

Get full access to this article

View all access options for this article.

References

Chernoff

. Shiverer: an autosomal recessive mutant mouse with myelin deficiency. J Hered 1981;72: 128.

Bird

Farrell

Sumo

. Brain lipid composition of the shiverer mouse: genetic defect in myelin development. J Neurochem 1978;31: 387–91.

Rosenbluth

. Peripheral myelin in the mouse mutant shiverer. J Comp Neurol 1980;193: 729–39.

Rosenbluth

. Central myelin in the mouse mutant shiverer. J Comp Neurol 1980;194: 639–48.

Peterson

Bray

. Hypomyelination in the peripheral nervous system of the shiverer mice and in shiverer-normal chimera. J Comp Neurol 1984;227: 348–56.

Takahashi

Roach

Teplow

Prusiner

Hood

. Cloning and characterization of the myelin basic protein gene from mouse: one gene can encode both 14 kd and 18.5 kd MBPs by the alternate use of exons. Cell 1985;42: 139–48.

Readhead

Popko

Takahashi

. Expression of a myelin basic protein gene in transgenic shiverer mice: correction of the dysmyelinating phenotype. Cell 1987;48: 703–12.

Popko

Puckett

Lai

. Myelin deficient mice: expression of myelin basic protein and generation of mice with varying levels of myelin. Cell 1987;48: 713–21.

Readhead

Hood

. The dysmyelinating mouse mutations shiverer (shi) and myelin deficient (shi^mld). Behav Genet 1990;20: 213–34.

10.

Biddle

March

Miller

. Research News. Mouse News Lett 1973;48: 24.

11.

Fraher

Delanty

FJN

. The development of the central-peripheral transitional zone of the rat cochlear nerve. A light microscopic study. J Anat 1987;155: 109–18.

12.

Darnell

Lodish

Baltimore

. Molecular cell biology. 2nd ed. New York, NY: Scientific American Books, 1990: 768–80.

13.

Hudson

Friedrich

Behar

Dubois-Dalcq

Lazzarini

. The initial events in myelin synthesis: orientation of proteolipid protein in the plasma membrane of cultured oligodendrocytes. J Cell Biol 1989;109: 717–27.

14.

Gamble

. Spinal and cranial nerve roots. In: Landon

, ed. The peripheral nerve. London, England: Chapman and Hall, 1976: 330–54.

15.

Corneliuson

Berthold

Fabreicius

Gatzinsky

Caristedt

. Marchi-positive myelinoid bodies at the transition between the central and the peripheral nervous system in some vertebrates. J Anat 1989;163: 17–31.

16.

Starr

Amile

Martin

Sanders

. Development of auditory function in newborn infants revealed by auditory brainstem potentials. Pediatrics 1977;60: 831–9.

17.

Starr

Achor

. Auditory brainstem responses in neurological disease. Arch Neurol 1975;32: 761–8.

18.

Henry

Haythorn

. Effects of age and stimulus intensity of the far field auditory brainstem potentials in the laboratory mouse. Dev Psychobiol 1978;11: 161–8.

19.

Henry

. Differential changes of auditory nerve and brain stem short latency evoked potentials in the laboratory mouse. Electroencephalogr Clin Neurophysiol 1979;46: 452–9.

20.

Gold

Cahani

Sohmer

Horowitz

Shahar

. Effects of body temperature elevation on auditory nerve-brain-stem evoked responses and EEGs in rats. Electroencephalogr Clin Neurophysiol 1985;60: 146–53.

21.

Church

Gritzke

. Effects of ketamine anesthesia on the rat brainstem auditory evoked potential as a function of dose and stimulus intensity. Electroencephalogr Clin Neurophysiol 1987;67: 570–83.

22.

Chen

. Effects of non-pathological factors on brain stem auditory evoked potentials in rats. Kaohsiung J Med Sci 1988;4: 553–64.

23.

Shah

Salamy

. Auditory-evoked far-field potentials in myelin deficient mutant quaking mice. Neuroscience 1980;5: 2321–3.

24.

Reardon

Pembrey

. The genetics of deafness. Arch Dis Child 1990;65: 1196–7.