Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory nerve output. Recent research has revealed a number of mechanisms that contribute to noise-induced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy. Contributions to TTS include reversible damage to hair cell (HC) stereocilia or synapses, while moderate TTS reflects protective purinergic hearing adaptation. PTS represents permanent damage to or loss of HCs and synapses. While the substrates of HC damage are complex, they include the accumulation of reactive oxygen species and the active stimulation of intracellular stress pathways, leading to programmed and/or necrotic cell death. Permanent damage to cochlear neurons can also contribute to the effects of NIHL, in addition to HC damage. These mechanisms have translational potential for pharmacological intervention and provide multiple opportunities to prevent HC damage or to rescue HCs and spiral ganglion neurons that have suffered injury. This paper reviews advances in our understanding of cellular mechanisms that contribute to NIHL and their potential for therapeutic manipulation.

Humans and chimpanzees share >99% identity in most proteins. One rare difference is a human-specific inactivating deletion in the CMAH gene, which determines biosynthesis of the sialic acid N-glycolylneuraminic acid (Neu5Gc). Since Neu5Gc is prominent on most chimpanzee cell surfaces, this mutation could have affected multiple systems. However, Neu5Gc is found in human cancers and fetuses and in trace amounts in normal human tissues, suggesting an alternate biosynthetic pathway. We inactivated the mouse Cmah gene and studied the in vivo consequences. There was no evidence for an alternate pathway in normal, fetal, or malignant tissue. Rather, null fetuses accumulated Neu5Gc from heterozygous mothers and dietary Neu5Gc was incorporated into oncogene-induced tumors. As with humans, there were accumulation of the precursor N-acetylneuraminic acid and increases in sialic acid O acetylation. Null mice showed other abnormalities reminiscent of the human condition. Adult mice showed a diminished acoustic startle response and required higher acoustic stimuli to increase responses above the baseline level. In this regard, histological abnormalities of the inner ear occurred in older mice, which had impaired hearing. Adult animals also showed delayed skin wound healing. Loss of Neu5Gc in hominid ancestors ∼2 to 3 million years ago likely had immediate and long-term consequences for human biology.

Acetylcholine has long been thought to be the neurotransmitter of the cochlear efferent system in mammals although the evidence is largely indirect. By using whole-cell recordings from isolated outer hair cells, we show that acetylcholine activates a large rapidly desensitizing outward potassium current. This corresponds to hyperpolarization of the membrane potential from rest. The half maximal dose for acetylcholine was 13.5 $\mu $M with a cooperativity of 2. The response was not due to a conventional muscarinic action of acetylcholine for it was not blocked by 0.1 $\mu $M atropine and muscarinic antagonists but it could be blocked by 0.1 $\mu $M curare, suggesting that it shared many properties of a nicotinic receptor. It was, however, inhibited by 10 $\mu $M strychnine. The potassium current activated by acetylcholine required external calcium and was characterized by a significant delay at room temperature. This points to the involvement of a second messenger system, possibly calcium itself.

Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to thepejvakingene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the humanpejvakingene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, thepejvakinallele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the humanpejvakingene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated withpejvakinmutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease.