Differential Effects of AAV.BDNF and AAV.Ntf3 in the Deafened Adult Guinea Pig Ear (original) (raw)

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. C ochlear implants (CI) restore the hearing sense by directly stimulating remnant auditory neural structures in ears in which hair cells are absent or dysfunctional. CIs have been very successful in restoring the recipient's ability to understand speech in quiet settings. However, they have had more limited benefit in restoring the ability to clearly perceive more complex acoustic stimuli, such as speech in background noise or music. Current CIs typically have 8-22 electrodes, but some studies have shown an effective functional yield of only 4-10 perceptual channels, which is likely due to current spread and the deterioration of auditory neuronal structures 1,2. A greater number of functional perceptual channels are required to optimize speech understanding in noise (up to 20) and music appreciation (32 or more) 1,3,4. Advances in CI technology, alone, cannot provide the necessary additional perceptual channels, as the improved technology does not address the issue of compromised auditory neural targets. To address this issue, 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. Neurotrophins are a family of molecules essential in the development and maintenance of neural systems throughout the body. Neurotrophin-3 (NT-3) and brain derived neurotrophic factor (BDNF) are the two neurotrophins critical for the normal development and function of the peripheral auditory nervous system 5. 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 BDNF is critical in the development of primarily vestibular ganglion cells and a minority of afferent PAFs 7. Additional null mutant mouse studies have suggested that there is a gradient of neurotrophin expression within the cochlea that changes over the course of development. BDNF is initially expressed primarily in the apex of the cochlea, with progressively increased expression in the base later in development 8. In contrast, NT-3 is primarily expressed in the cochlear base early in development, and expression progresses apically in post-natal and adult mice 8,9. Within the adult inner ear, NT-3 is primarily expressed by inner hair cells and supporting cells within the cochlear apex 9 , and BDNF is primarily expressed within the vestibular system 5 .