title: Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy.
abstract: Mutations in the connexin 26 gene (GJB2) are the most common genetic cause of deafness, leading to congenital bilateral non-syndromic sensorineural hearing loss. Here we report the generation of a mouse model for a connexin 26 (Cx26) mutation, in which cre-Sox10 drives excision of the Cx26 gene from non-sensory cells flanking the auditory epithelium. We determined that these conditional knockout mice, designated Gjb2-CKO, have a severe hearing loss. Immunocytochemistry of the auditory epithelium confirmed absence of Cx26 in the non-sensory cells. Histology of the organ of Corti and the spiral ganglion neurons (SGNs) performed at ages 1, 3, or 6 months revealed that in Gjb2-CKO mice, the organ of Corti began to degenerate in the basal cochlear turn at an early stage, and the degeneration rapidly spread to the apex. In addition, the density of SGNs in Rosenthal's canal decreased rapidly along a gradient from the base of the cochlea to the apex, where some SGNs survived until at least 6 months of age. Surviving neurons often clustered together and formed clumps of cells in the canal. We then assessed the influence of brain derived neurotrophic factor (BDNF) gene therapy on the SGNs of Gjb2-CKO mice by inoculating Adenovirus with the BDNF gene insert (Ad.BDNF) into the base of the cochlea via the scala tympani or scala media. We determined that over-expression of BDNF beginning around 1 month of age resulted in a significant rescue of neurons in Rosenthal's canal of the cochlear basal turn but not in the middle or apical portions. This data may be used to design therapies for enhancing the SGN physiological status in all GJB2 patients and especially in a sub-group of GJB2 patients where the hearing loss progresses due to ongoing degeneration of the auditory nerve, thereby improving the outcome of cochlear implant therapy in these ears.
authors: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 West. Medical Center Dr., Ann Arbor, MI 48109-5648, USA; Department of Otolaryngology, Kansai Medical University, 2-3-1, Shinmachi, Hirakata, Osaka 573-1191, Japan.
authors: Yohei
authors: Y
authors: Takada
authors: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 West. Medical Center Dr., Ann Arbor, MI 48109-5648, USA.
authors: Lisa A
authors: LA
authors: Beyer
authors: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 West. Medical Center Dr., Ann Arbor, MI 48109-5648, USA.
authors: Donald L
authors: DL
authors: Swiderski
authors: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 West. Medical Center Dr., Ann Arbor, MI 48109-5648, USA.
authors: Aubrey L
authors: AL
authors: O'Neal
authors: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 West. Medical Center Dr., Ann Arbor, MI 48109-5648, USA.
authors: Diane M
authors: DM
authors: Prieskorn
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Shaked
authors: S
authors: Shivatzki
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Karen B
authors: KB
authors: Avraham
authors: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 West. Medical Center Dr., Ann Arbor, MI 48109-5648, USA. Electronic address: yoash@umich.edu.
authors: Yehoash
authors: Y
authors: Raphael
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000367:Age Factors; D000818:Animals; D001309:Auditory Threshold; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D000072259:Connexin 26; D017630:Connexins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009925:Organ of Corti / Q000378:metabolism / Q000473:pathology; D013136:Spiral Ganglion / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D000072259:Connexin 26