Signaling through erbB receptors is a critical functional regulator in the mature cochlea.
Noise, ototoxic substances and various genetic factors are common causes of profound hearing loss. Cochlear implants can often restore hearing in these cases, but only if a sufficient number of responsive auditory nerve fibers remain. Over time, these nerve fibers degenerate in the damaged ear, and it is therefore important to establish factors that control neuronal survival and maintain neural excitability. Recent studies show that neuregulins and their receptors are important for survival and proper targeting of neurons in the developing inner ear. A role for neuregulins as maintainers of the neuronal population in the mature inner ear was therefore hypothesized. Here, this hypothesis was directly tested by chronic local application of substances that block neuregulin receptors. Using auditory brainstem response measurements, we demonstrate that such receptor block leads to a progressive hearing impairment that develops over the course of weeks. This impairment occurs despite a normal number of auditory neurons and preserved outer hair cell function. Real-time quantitative reverse transcriptase-polymerase chain reaction shows alterations in neurotrophin-3 expression, suggesting that this growth factor participates in regulating cochlear sensitivity. The present work demonstrates the critical importance of neuregulin/erbB signaling in long-term functional regulation in the mature guinea pig hearing organ.
Watanabe
Futoshi
F
Center for Hearing and Communication Research and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Kirkegaard
Mette
M
Matsumoto
Suguru
S
Gont
Cecilia
C
Mannström
Paula
P
Ulfendahl
Mats
M
Fridberger
Anders
A
D000818:Animals; D002452:Cell Count / Q000379:methods; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000502:physiology*; D008845:Microinjections; D020933:Neurotrophin 3 / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism; D013136:Spiral Ganglion / Q000033:anatomy & histology / Q000187:drug effects; D013997:Time Factors
C433938:4557 W; D020933:Neurotrophin 3; D011799:Quinazolines; D017470:Receptors, Glutamate; D020794:Receptor Protein-Tyrosine Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline