BDNF mRNA expression and protein localization are changed in age-related hearing loss
Introduction
During the mammalian life span, there are significant changes in the ability to perceive and process external sounds [9], [11], [13], [14]. The overall age-related loss of hair cells and spiral ganglion cells in the cochlea is of varying magnitude depending on species or strain [3], [20], [30], [31], [45], [49], [56], [65]. Evidence that the auditory periphery is clearly affected by age [18], [31] concurs with multiple investigations that show auditory brainstem structures to exhibit substantial deficits in neuronal processing over age in humans [11], [25], [29], [32], [33], [41] and rodents [18], [27], [28], [51], [63], [66]. In the auditory system presbycusis [9], [12] is associated with specific plastic alterations [18], [27], [51], [63], [66]. Following an ELISA based approach on whole cochlear tissue in the inner ear of aging rodents, however, no alteration of BDNF protein level was observed [43].
Novel studies indicate that age-related BDNF expression changes may be restricted to a loss of the activity-dependent component of BDNF [4], [5], [58]. Following transmitter and/or Ca2+-dependent activation of diverse signalling cascades, the individual promoters of the four untranslated BDNF exons I–IV are differentially used [23], [59], [68], [69], [71], [78]. As the activity-dependent component of BDNF mRNA is not necessarily linked to the overall BDNF protein level [5], the concurrent detection of the distinct BDNF transcripts may be required to obtain insight into the altered expression of BDNF.
The expression of BDNF has been extensively studied in the brain and the activity-dependent usage of exons III and IV promoters has been well described [59], [68], [69], [71]. In the inner ear the role of BDNF has been studied and is known to be required for the survival of vestibular ganglion and type II spiral ganglion neurons [19], [50], [54]. From our analysis of mouse mutants, we recently concluded that a reduction of BDNF signalling in the postnatal cochlea leads to a loss of OHC innervation in the basal part of the cochlea and hearing loss [54]. This phenotype was explained by the disruption of a gradient of BDNF transcripts along the tonotopic axis of the cochlea with the highest concentration in the midbasal and basal turn [54]. The phenotypic similarities observed between mouse mutants lacking BDNF signalling and aged animals with hearing loss (loss of afferent type II innervation on OHCs in the midbasal/basal part of the cochlea) prompted us to analyse BDNF expression in aged animals.
Here, we describe for the first time the co-expression of distinct BDNF transcripts and BDNF protein in adult cochleae. Analysing the expression of BDNF mRNA and protein in animal models of presbycusis, reduced levels of BDNF transcripts were observed in cochlear neurons during aging. This was associated with reduced BDNF protein in peripheral and central cochlear neurites. The data are discussed in the context of a function of targeted BDNF in cochlear neurites for maintenance of normal OHCs or brainstem synapses, and the integrity of plasticity performance over age.
Section snippets
Animals
Fischer 344 rats and Mongolian gerbils (Meriones unguiculatus) were purchased from Interfauna (Tuttlingen, Germany) and were housed for 2–3.5 years in an animal care facility, where 50–60 dB SPL noise levels were not exceeded.
The care and use of the animals during the course of this study were carried out in accordance with the ethical guidelines prescribed by the University of Tübingen. In order to comply fully with the guidelines concerning experimentation with healthy animals, the study
Age-related hearing loss in Fisher 344 rats and Mongolian gerbils
The following results summarize data from an ongoing study on age-related hearing loss, which has lasted for more than 10 years. To define the morphological and molecular changes associated with age-related hearing loss, we used two well-established rodent models, Fischer 344 rats and Mongolian gerbils [20], [30]. Animals were raised under low noise levels and both frequency-dependent and click-evoked auditory brainstem response measurements were performed every 3–6 months as described under
Discussion
We have investigated the long-term changes in BDNF mRNA and protein expression in the adult mammalian auditory system. The animals were observed and tested over their natural life span, with the majority of animals displaying an age-related hearing loss. Changes in BDNF expression, both at the RNA and protein level were observed in these animals. While a causal relationship between changes in BDNF gene expression and hearing loss may remain uncertain, the documented role of BDNF as an effector
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft DFG-SFB444, DFG Kni 316/3-2 and Fortüne Kni-F1251236, Fortüne Kni-F12512 79, Fortüne 816-0-0 and the Spanish MEC.
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These authors equally contributed to the manuscript.