PMID- 24333301 OWN - NLM STAT- MEDLINE DCOM- 20140929 LR - 20220318 IS - 1878-5891 (Electronic) IS - 0378-5955 (Print) IS - 0378-5955 (Linking) VI - 309 DP - 2014 Mar TI - Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. PG - 124-35 LID - S0378-5955(13)00282-7 [pii] LID - 10.1016/j.heares.2013.11.009 [doi] AB - 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. CI - Copyright (c) 2013 Elsevier B.V. All rights reserved. FAU - Takada, Yohei AU - Takada Y AD - 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. FAU - Beyer, Lisa A AU - Beyer LA AD - 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. FAU - Swiderski, Donald L AU - Swiderski DL AD - 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. FAU - O'Neal, Aubrey L AU - O'Neal AL AD - 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. FAU - Prieskorn, Diane M AU - Prieskorn DM AD - 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. FAU - Shivatzki, Shaked AU - Shivatzki S AD - Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. FAU - Avraham, Karen B AU - Avraham KB AD - Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. FAU - Raphael, Yehoash AU - Raphael Y AD - 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. LA - eng GR - R01 DC011835/DC/NIDCD NIH HHS/United States GR - R01 DC007634/DC/NIDCD NIH HHS/United States GR - P30 DC005188/DC/NIDCD NIH HHS/United States GR - R01 DC010412/DC/NIDCD NIH HHS/United States GR - R55 DC007634/DC/NIDCD NIH HHS/United States GR - R01-DC011835/DC/NIDCD NIH HHS/United States GR - R01-DC010412/DC/NIDCD NIH HHS/United States GR - P30-DC05188/DC/NIDCD NIH HHS/United States GR - R01-DC007634/DC/NIDCD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131212 PL - Netherlands TA - Hear Res JT - Hearing research JID - 7900445 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Connexins) RN - 0 (GJB2 protein, human) RN - 0 (Gjb2 protein, mouse) RN - 127120-53-0 (Connexin 26) SB - IM MH - Adenoviridae/genetics MH - Age Factors MH - Animals MH - Auditory Threshold MH - Brain-Derived Neurotrophic Factor/*biosynthesis/genetics MH - Connexin 26 MH - Connexins/*deficiency/genetics MH - Disease Models, Animal MH - Evoked Potentials, Auditory, Brain Stem MH - Female MH - Gene Transfer Techniques MH - Genetic Therapy/*methods MH - Genetic Vectors MH - Hearing Loss, Sensorineural/genetics/metabolism/pathology/physiopathology/*therapy MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nerve Degeneration MH - Neurons/*metabolism/pathology MH - Organ of Corti/metabolism/pathology MH - Spiral Ganglion/*metabolism/pathology/physiopathology PMC - PMC3946535 MID - NIHMS549566 EDAT- 2013/12/18 06:00 MHDA- 2014/09/30 06:00 PMCR- 2015/03/01 CRDT- 2013/12/17 06:00 PHST- 2013/07/12 00:00 [received] PHST- 2013/11/16 00:00 [revised] PHST- 2013/11/19 00:00 [accepted] PHST- 2013/12/17 06:00 [entrez] PHST- 2013/12/18 06:00 [pubmed] PHST- 2014/09/30 06:00 [medline] PHST- 2015/03/01 00:00 [pmc-release] AID - S0378-5955(13)00282-7 [pii] AID - 10.1016/j.heares.2013.11.009 [doi] PST - ppublish SO - Hear Res. 2014 Mar;309:124-35. doi: 10.1016/j.heares.2013.11.009. Epub 2013 Dec 12.