Differential effects of AAV.BDNF and AAV.Ntf3 in the deafened adult guinea pig ear.

Cameron L Budenz,Seiji B Shibata,Hiu Tung Wong,Donald L Swiderski,Bryan E Pfingst,Yehoash Raphael

doi:10.1038/srep08619

Cameron L Budenz, Seiji B Shibata + Show 4 more

Open Access

https://doi.org/10.1038/srep08619

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Journal: Scientific reports	Publication Date: Mar 2, 2015
Citations: 55	License type: CC BY 4.0

Affiliation: University of Michigan–Ann Arbor

Abstract

Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV.BDNF and AAV.Ntf3, on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV.BDNF or AAV.Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term.

Highlights

Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, The University of Michigan, Ann Arbor, MI, USA
Studies using null mutant mice have demonstrated that NT-3 is essential for the normal development of the majority of spiral ganglion neurons (SGNs) and afferent peripheral auditory fibers (PAFs)[6,7], whereas brain derived neurotrophic factor (BDNF) is critical in the development of primarily vestibular ganglion cells and a minority of afferent PAFs7
Intracochlear infusion of neomycin led to a complete loss of hair cells throughout all cochlear turns and a loss of Deiters and pillar cells, leaving a flat epithelium throughout the basal turn

Summary

Introduction

It is likely that advances in biotherapies will be key to further enhancing CI outcomes It is through biotherapies, such as the delivery of neurotrophins to the inner ear, that auditory neural substrate survival and health may be improved, thereby increasing the number of perceptual channels rendered by our current CI electrode technology. Several laboratories have shown that administration of neurotrophin molecules to the deafened inner ear enhances SGN survival and health[10,11,12,13,14] These and other studies have found a beneficial short-term effect of neurotrophins on the auditory neural structures of the deafened inner ear (See Budenz et al for a recent review[15]). It has remained unclear whether any of these beneficial effects persist over the long-term, and whether one neurotrophin molecule is superior in its ability to enhance the survival and health of remnant auditory neural substrates in the deafened adult inner ear

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