Lack of Bdnf and TrkB signalling in the postnatal cochlea leads to a spatial reshaping of innervation along the tonotopic axis and hearing loss.
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.
Schimmang
Thomas
T
Center for Molecular Neurobiology Hamburg, University of Hamburg, Falkenreid, Hamburg, Germany.
Tan
Justin
J
Müller
Marcus
M
Zimmermann
Ulrike
U
Rohbock
Karin
K
Kôpschall
Iris
I
Limberger
Annette
A
Minichiello
Liliana
L
Knipper
Marlies
M
D000818:Animals; D027321:Anion Transport Proteins; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003051:Cochlea / Q000033:anatomy & histology / Q000254:growth & development* / Q000294:innervation* / Q000378:metabolism; D005072:Evoked Potentials, Auditory; D006319:Hearing Loss, Sensorineural / Q000209:etiology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D020409:Molecular Motor Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D064531:Peripherins; D011506:Proteins / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000076988:Sulfate Transporters; D013569:Synapses / Q000378:metabolism
D027321:Anion Transport Proteins; D019208:Brain-Derived Neurotrophic Factor; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D020409:Molecular Motor Proteins; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D064531:Peripherins; C498720:Pres protein, mouse; D011506:Proteins; C498719:SLC26A5 protein, human; D000076988:Sulfate Transporters; D020813:Receptor, trkB