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The Journal of Neuroscience, March 29, 2006, 26(13):3541-3550; doi:10.1523/JNEUROSCI.2488-05.2006

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Behavioral/Systems/Cognitive
Nuclear Factor B Deficiency Is Associated with Auditory Nerve Degeneration and Increased Noise-Induced Hearing Loss

Hainan Lang,¹ Bradley A. Schulte,^1,2 Daohong Zhou,¹ Nancy Smythe,² Samuel S. Spicer,¹ and Richard A. Schmiedt²

¹Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, and ²Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina 29425

Correspondence should be addressed to Hainan Lang, Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Avenue, P.O. Box 250908, Charleston, SC 29425. Email: langh{at}musc.edu

Degeneration of the spiral ganglion neurons (SGNs) of the auditory nerve occurs with age and in response to acoustic injury. Histopathological observations suggest that the neural degeneration often begins with an excitotoxic process affecting the afferent dendrites under the inner hair cells (IHCs), however, little is known about the sequence of cellular or molecular events mediating this excitotoxicity. Nuclear factor B (NFB) is a transcription factor involved in regulating inflammatory responses and apoptosis in many cell types. NFB is also associated with intracellular calcium regulation, an important factor in neuronal excitotoxicity. Here, we provide evidence that NFB can play a central role in the degeneration of SGNs. Mice lacking the p50 subunit of NFB (p50^–/– mice) showed an accelerated hearing loss with age that was highly associated with an exacerbated excitotoxic-like damage in afferent dendrites under IHCs and an accelerated loss of SGNs. Also, as evidenced by immunostaining intensity, calcium-buffering proteins were significantly elevated in SGNs of the p50^–/– mice. Finally, the knock-out mice exhibited an increased sensitivity to low-level noise exposure. The accelerated hearing loss and neural degeneration with age in the p50^–/– mice occurred in the absence of concomitant hair cell loss and decline of the endocochlear potential. These results indicate that NFB activity plays an important role in protecting the primary auditory neurons from excitotoxic damage and age-related degeneration. A possible mechanism underlying this protection is that the NFB activity may help to maintain calcium homeostasis in SGNs.

Key words: hearing loss; spiral ganglion neuron; NFB; noise; excitotoxicity; cochlea

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Received Feb. 18, 2005; revised Jan. 24, 2006; accepted Jan. 16, 2006.

Correspondence should be addressed to Hainan Lang, Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Avenue, P.O. Box 250908, Charleston, SC 29425. Email: langh{at}musc.edu

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