Lack of Bdnf and TrkB signalling in the postnatal cochlea leads to a spatial reshaping of innervation along the tonotopic axis and hearing loss

Abstract

Members of the neurotrophin gene family and their high-affinity Trk receptors control innervation of the cochlea during embryonic development. Lack of neurotrophin signalling in the cochlea has been well documented for early postnatal animals, resulting in a loss of cochlear sensory neurones and a region-specific reduction of target innervation along the tonotopic axis. However, how reduced neurotrophin signalling affects the innervation of the mature cochlea is currently unknown. Here, we have analysed the consequences of a lack of the TrkB receptor and its ligand, the neurotrophin brain-derived neurotrophic factor (Bdnf), in the late postnatal or adult cochlea using mouse mutants. During early postnatal development, mutant animals show a lack of afferent innervation of outer hair cells in the apical part of the cochlea,whereas nerve fibres in the basal part are maintained. Strikingly, this phenotype is reversed during subsequent maturation of the cochlea, which results in a normal pattern of outer hair cell innervation in the apex and loss of nerve fibres at the base in adult mutants. Measurements of auditory brain stem responses of these mice revealed a significant hearing loss. The observed innervation patterns correlate with opposing gradients of Bdnf and Nt3 expression in cochlear neurones along the tonotopic axis. Thus, the reshaping of innervation may be controlled by autocrine signalling between neurotrophins and their receptors in cochlear neurones. Our results indicate a substantial potential for re-innervation processes in the mature cochlea,which may also be of relevance for treatment of hearing loss in humans.

Deletion of the Ca2+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

“…8), occupying the same region as the SK2 channel (17), suggests a vital role of the BK current in the efferent inhibitory control. Whatever the function of BK on OHCs level, the similarity of basal to apical declining gradients of BK expression (present study) and the gradient of efferents (26) and presumptively afferent type II (22) indicates that BK channels play a role in maintaining those OHCs that receive efferent inhibitory feedback from the brain.…”

“…Hearing Measurements. Anesthesia of animals, measurements of auditory brainstem responses (ABR), and distortion products of the otoacoustic emissions (DPOAE) were performed as described (22,23).…”

“…Cochleae were isolated, dissected, fixed, cryosectioned, and stained as described (16,22,23). Anti-BK␣ (polyclonal anti-rabbit, Alomone Labs, Jerusalem; APC-021) and anti-BK␣ polyclonal antibody, recently generated (25), were used with similar results.…”

Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3:In VivoEvidence

“…Anesthesia of animals, measurements of auditory brainstem responses (ABRs), and the cubic distortion product of the otoacoustic emissions (DPOAEs) were performed as described previously (Knipper et al, 2000;Schimmang et al, 2003;Carnicero et al, 2004). Briefly, ABR thresholds were determined with click (100 s) or pure tone stimuli (2-45 kHz).…”

Role of BDNF and neurotrophic receptors in human inner ear development

“…In late post-natal stages of these mutant mice, a lack of afferent innervation in the apical part of the cochlea has been shown, while the basal portion was unaffected but in older stages, the opposite was true. The reshaping of innervation was probably regulated by autocrine signaling between neurotrophins and their receptors in cochlear neurons (Schimmang, et al 2003). Embryonic inner ear developmental in chick (Hallbook and Fritzsch 1997) and murines (Ernfors et al 1994) has also revealed the biological significance of BDNF expression for both afferent and efferent fiber innervation.…”