Nuclear Factor κB Deficiency Is Associated with Auditory Nerve Degeneration and Increased Noise-Induced Hearing Loss

Abstract

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 Ϫ/Ϫ 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 Ϫ/Ϫ 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 Ϫ/Ϫ 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.

A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti

“…They also complement the many other recent studies that have documented signal transduction pathways leading to hair death due to a variety of stressors, including aminoglycosides (e.g., Pirvola et al 2000;Bodmer et al 2002a), cisplatin (e.g., Zhang et al 2003;Wang et al 2004), and noise exposure (e.g., Harris et al 2005;Lang et al 2006).…”

c-Ret–mediated hearing loss in mice with Hirschsprung disease

“…In the case of immunohistochemical estimation of phosphorylated protein, percentage (mean ± SE) was calculated by dividing the number of phosphorylated SGNs by the number of the protein-expressing SGNs in each Rosenthal's canal from three or four mice for each mouse strain. Estimation of the cell density of SGNs with Kluver-Barrera staining basically followed the previous method (35,36). In brief, the area of Rosenthal's canal in five sections from each mouse was measured with the software program WinROOF.…”

“…Preparation of tissues for TEM basically followed the previous method (35). In brief, after perfusion fixation with a fixative solution I containing 2% (vol/vol) paraformaldehyde, 2% (vol/vol) glutaraldehyde and 0.3 M Hepes (pH 7.4), dissected murine cochleae were immersed in the same fixative solution overnight at 4°C.…”

Transplantation of Mouse Embryonic Stem Cells into the Cochlea of an Auditory-Neuropathy Animal Model: Effects of Timing after Injury

“…The methods for recording the compound action potential (CAP) response, distortion product otoacoustic emissions (DPOAEs), and endocochlear potential (EP) were similar to those previously described (Lang et al 2005(Lang et al , 2006. Physiological data were obtained from ESC-implanted ears and a group of untreated ears.…”

“…CD45R (RA3-6B2) is a rat monoclonal IgG2a antibody raised against an extracelluar domain of the transmembrane glycoprotein CD45 and is expressed broadly among hematopoietic cells including macrophages and microglia (Bhave et al 1998). Monoclonal anti-neurofilament 200 reacts with a single 200-kDa band in both alkaline phosphatase dephosphorylated and untreated preparations of rat spinal cord (manufacturer's technical information from Sigma) and specifically stains nerve fibers in the inner ear (Lang et al 2006;Wise et al 2005). The GFAP monoclonal antibody recognizes a 50-kDa band by immunoblotting (manufacturer's technical information from Chemicon) and has been used extensively to label astrocytes and neoplastic cells of glial lineage in the central nervous system (McLendon and Bigner 1994;Kasischke et al 2006;Ward et al 2004).…”