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The Journal of Neuroscience, October 6, 2004, 24(40):8651-8661; doi:10.1523/JNEUROSCI.0733-04.2004

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Development/Plasticity/Repair
Survival of Adult Spiral Ganglion Neurons Requires erbB Receptor Signaling in the Inner Ear

Konstantina Stankovic,^1,3 * Carlos Rio,^1 * Anping Xia,¹ Mitsuru Sugawara,^1,3,4 Joe C. Adams,³ M. Charles Liberman,³ and Gabriel Corfas^1,2

¹Division of Neuroscience, Children's Hospital, Boston, Massachusetts 02115, ²Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, ³Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114-3096, and ⁴Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan

Degeneration of cochlear sensory neurons is an important cause of hearing loss, but the mechanisms that maintain the survival of adult cochlear sensory neurons are not clearly defined. We now provide evidence implicating the neuregulin (NRG)-erbB receptor signaling pathway in this process. We found that NRG1 is expressed by spiral ganglion neurons (SGNs), whereas erbB2 and erbB3 are expressed by supporting cells of the organ of Corti, suggesting that these molecules mediate interactions between these cells. Transgenic mice in which erbB signaling in adult supporting cells is disrupted by expression of a dominant-negative erbB receptor show severe hearing loss and 80% postnatal loss of type-I SGNs without concomitant loss of the sensory cells that they contact. Quantitative RT-PCR analysis of neurotrophic factor expression shows a specific downregulation in expression of neurotrophin-3 (NT3) in the transgenic cochleas before the onset of neuronal death. Because NT3 is critical for survival of type I SGNs during development, these results suggest that it plays similar roles in the adult. Together, the data indicate that adult cochlear supporting cells provide critical trophic support to the neurons, that survival of postnatal cochlear sensory neurons depends on reciprocal interactions between neurons and supporting cells, and that these interactions are mediated by NRG and neurotrophins.

Key words: neuregulin; cochlea; hearing; GDNF; neurotrophin; erbB

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Received March 1, 2004; revised July 30, 2004; accepted August 17, 2004.

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