Endocochlear potential contributes to hair cell death in TMPRSS3 hearing loss

Area of Science:

• Genetics and Molecular Biology
• Otolaryngology
• Neuroscience

Background:

• Pathogenic variants in TMPRSS3 are a frequent cause of human hearing loss.
• The precise molecular mechanisms underlying TMPRSS3-related hearing impairment are not fully understood.
• Tmprss3Y260X/Y260X mice show normal early development but rapid hair cell death at hearing onset.

Purpose of the Study:

• To investigate the role of extracellular factors, specifically endocochlear potential (EP), in hair cell death in TMPRSS3-related hearing loss.
• To explore potential therapeutic strategies targeting EP for TMPRSS3-related hearing loss.

Main Methods:

• Analysis of Tmprss3Y260X/Y260X mouse models.
• In vitro studies using cochlear explants.
• In vivo studies involving genetic crosses and pharmacological intervention (furosemide).
• Measurement of endocochlear potential (EP).

Main Results:

• Tmprss3Y260X/Y260X mice exhibit a transient increase in EP before hair cell death.
• Reducing EP, through genetic modification or furosemide treatment, significantly improved hair cell survival.
• In vitro and in vivo experiments confirmed the protective effect of EP reduction on hair cells.

Conclusions:

• Endocochlear potential (EP) plays a critical role in hair cell survival in the context of TMPRSS3-related hearing loss.
• Elevated EP may contribute to hair cell death in these models.
• Modulating EP presents a promising therapeutic avenue for treating TMPRSS3-related hearing loss.