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      Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma

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          Abstract

          Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreER T line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury.

          DOI: http://dx.doi.org/10.7554/eLife.03564.001

          eLife digest

          Noise-induced hearing loss is common, and can result from prolonged exposure to moderate levels of noise that are not perceived as painful or even unpleasant. Some hearing loss can be attributed to the death of hair cells in a part of the inner ear called the cochlea. When sound waves hit the cochlea, they cause the fluid inside it to vibrate: the hair cells detect these vibrations and convert them into electrical signals that are sent along neurons to the brain. However, vibrations that are too strong can destroy hair cells.

          Increasing evidence suggests that hearing loss also results from damage to the synapses that connect the hair cells and the neurons in the cochlea. During development of the inner ear, molecules called growth factors are needed to ensure the survival of these neurons. Wan et al. predicted that these growth factors might also have a role in adult animals, and that producing more of them might help to safeguard hearing from the damaging effects of noise.

          Consistent with this, mice that were genetically modified to lack a growth factor called neurotrophin-3 had cochleae that did not work properly and had fewer synapses between hair cells and neurons compared to control mice. Conversely, mice that produced too much neurotrophin-3 had more synapses than controls and also recovered more quickly from the effects of 2 hr exposure to 100 dB noise (roughly the volume of a pneumatic drill). Studies of the cochlea revealed that the extra neurotrophin-3 had boosted the regeneration of synapses damaged by the noise.

          The beneficial effects of neurotrophin-3 were still seen when overproduction was started shortly after noise exposure, suggesting that it could have therapeutic potential. This is particularly significant in the light of recent evidence that the loss of synapses often comes before the death of hair cells in both age-related hearing loss and noise-induced hearing loss.

          DOI: http://dx.doi.org/10.7554/eLife.03564.002

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          Most cited references 53

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          A robust and high-throughput Cre reporting and characterization system for the whole mouse brain

          The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universal responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in a number of Cre-driver lines, including novel Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.
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            Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline.

            Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.
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              The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression.

              Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MeCP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in Mecp2 mutant mice, and deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the Mecp2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in Mecp2 mutants. Our results provide in vivo evidence for a functional interaction between Mecp2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.
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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                20 October 2014
                2014
                : 3
                Affiliations
                [1 ]F M Kirby Neurobiology Center, Boston Children's Hospital , Boston, United States
                [2 ]Department of Neurology, Harvard Medical School , Boston, United States
                [3 ]Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan , Ann Arbor, United States
                [4 ]Department of Otology and Laryngology, Harvard Medical School , Boston, United States
                [5 ]Eaton Peabody Laboratories, Massachusetts Eye and Ear Infirmary , Boston, United States
                The Hospital for Sick Children Research Institute, University of Toronto , Canada
                The Hospital for Sick Children Research Institute, University of Toronto , Canada
                Author notes
                [* ]For correspondence: corfas@ 123456med.umich.edu
                [†]

                Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, United States.

                Article
                03564
                10.7554/eLife.03564
                4227045
                25329343
                Copyright © 2014, Wan et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: National Institute on Deafness and Other Communication Disorders FundRef identification ID: http://dx.doi.org/10.13039/100000055
                Award ID: R01 DC 004820
                Award Recipient :
                Funded by: National Institute of Child Health and Human Development FundRef identification ID: http://dx.doi.org/10.13039/100000071
                Award ID: P30- HD 18655 (Mental Retardation Research Center)
                Award Recipient :
                Funded by: Hearing Health Foundation FundRef identification ID: http://dx.doi.org/10.13039/100002046
                Award Recipient :
                Funded by: National Institute on Deafness and Other Communication Disorders FundRef identification ID: http://dx.doi.org/10.13039/100000055
                Award ID: P30 DC 005209
                Award Recipient :
                Funded by: Boston Children's Hospital FundRef identification ID: http://dx.doi.org/10.13039/100006823
                Award ID: Department of Otolaryngology
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                0.8
                Overexpression of the growth factor neurotrophin-3 helps to repair noise-induced damage in the mouse inner ear by promoting the regeneration of damaged synapses.

                Life sciences

                deafness, synaptogenesis, hearing loss, neuron–glia interactions, glial cell, mouse

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