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.

Auditory brainstem responses in 10 inbred strains of mice

“…As reported in previous studies (Chuu et al, 2001;Fujiyoshi et al, 1994;Hunter and Willott, 1987;Parham et al, 2001;Zheng et al, 1999), the ABR patterns of mice typically consisted of five vertical positive waves (Figs. 1A-1, B-1).…”

“…Moreover, the measurement of ABR threshold has proven essential in identifying modifier genes (Ikeda et al, 2002;Johnson and Zheng, 2002;Johnson et al, 2000Johnson et al, , 2001Noben-Trauth et al, 1997Zheng and Johnson, 2001). However, previous studies have shown that, while some hearing impairments were characterized by significant changes in all ABR parameters such as the threshold, amplitude, and latency, others were associated with the abnormalities in the amplitude and latency but not the threshold (Evans et al, 1983;Fujiyoshi et al, 1994;Kanzaki et al, 1985). For example, Kanzaki et al (1985) have shown that the peak latency of later ABR waves for the shiverer mice was prolonged with increased inter-peak latency although the threshold was normal.…”

Deafness inClaudin 11-Null Mice Reveals the Critical Contribution of Basal Cell Tight Junctions to Stria Vascularis Function

“…Finally, for genetic mutant mice exhibiting moderate to severe CNS or PNS hypomyelination, ABRs are distinct from those observed in Claudin 11-null mice. For example, three myelin mutants examined by other groups exhibit significantly increased latencies for Peak I (Zhou et al, 1995a,b) or Peaks I-V (Fujiyoshi et al, 1994), whereas Peak V latency is longer in Claudin 11-null mice and Peaks I-III are indistinguishable from controls.…”

CNS Myelin Paranodes Require Nkx6-2 Homeoprotein Transcriptional Activity for Normal Structure

“…To determine whether the rotarod phenotype might be associated with changes in conduction velocity in the CNS of Nkx6-2 null mice, we examined evoked potentials derived from ABRs in a manner similar to that of previous studies (Fujiyoshi et al, 1994;Gow et al, 2004). Presentation of 102 sec pure tone pips into the auditory canals of anesthetized mice at different sound pressure levels elicits a series of EEGs comprising five or six well resolved peaks with latencies ϳ1 msec apart (Fig.…”