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.
The genes for ␣-and -tectorin encode the major noncollagenous proteins of the tectorial membrane. Recently, a targeted deletion of the mouse ␣-tectorin gene was found to cause loss of cochlear sensitivity (1). Here we describe that mRNA levels for -tectorin, but not ␣-tectorin, are significantly reduced in the cochlear epithelium under constant hypothyroid conditions and that levels of -tectorin protein in the tectorial membrane are lower. A delay in the onset of thyroid hormone supply prior to onset of hearing, recently described to result in permanent hearing defects and loss of active cochlear mechanics (2), can also lead to permanently reduced -tectorin protein levels in the tectorial membrane. -Tectorin protein levels remain low in the tectorial membrane up to one year after the onset of thyroid hormone supply has been delayed until postnatal day 8 or later and are associated with an abnormally structured tectorial membrane and the loss of active cochlear function. These data indicate that a simple delay in thyroid hormone supply during a critical period of development can lead to low -tectorin levels in the tectorial membrane and suggest for the first time that -tectorin may be required for development of normal hearing.It has been known for many years that thyroid hormone (TH) 1 is necessary for normal development of the auditory system (3-5). Both genetic and acquired neonatal TH deficiency may result in a profound mental disability that is often accompanied by deafness. The existence of various TH-sensitive periods during inner ear development and the success of delayed, corrective TH treatment has recently been investigated (2, 6). These studies revealed that maternal TH prior to the onset of thyroid gland function, as well as TH supply beyond the onset of hearing at postnatal day 12 (P12), was not critical for the development of normal hearing in rats (2, 6). However, within the crucial period of time any delay in the rise of TH plasma levels (transient hypothyroidism) leads to permanent hearing defects, though the organ of Corti develops to an organ without obvious structural or neuronal abnormalities (2). Analysis of distortion product otoacoustic emissions revealed that the active cochlear process was TH-dependent and was permanently lost following the induction of a transient TH-free period between E17 and ϾP8 (2). Distortion product otoacoustic emissions are sounds that emanate from the ear and are believed to be produced by the interaction of actively amplified traveling waves on the basilar membrane (7-9). The tectorial membrane plays a crucial role in this active process, because it couples transverse, sound-induced, basilar membrane motion to a radial deflection of the sensory hair bundles. In former studies with rodents (10, 11) it has been observed that the tectorial membrane is distorted as a result of constant hypothyroidism. The major non-collagenous components of the tectorial membrane, ␣-and -tectorin, were identified recently as the products of single copy genes (12). Missen...
Pathological auditory brainstem responses (lack of responses, elevated thresholds and perturbed waveforms) in combination with present otoacoustic emissions are typical audiometric findings in patients with a hearing impairment that particularly affects speech comprehension or complete deafness. This heterogenous group of disorders first described as "auditory neuropathy" includes dysfunction of peripheral synaptic coding of sound by inner hair cells (synaptopathy) and/or of the generation and propagation of action potentials in the auditory nerve (neuropathy). This joint statement provides prevailing background information as well as recommendations on diagnosis and treatment. The statement focuses on the handling in the german language area but also refers to current international statements.
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