TMC function, dysfunction, and restoration in mouse vestibular organs

Area of Science:

• Neuroscience
• Genetics
• Otolaryngology

Background:

• TMC1 and TMC2 are essential for mechanosensory transduction in the inner ear.
• Their precise roles and expression patterns in vestibular organs require further investigation.

Purpose of the Study:

• To investigate the expression and function of TMC1 and TMC2 in vestibular organs.
• To determine the impact of TMC1 and TMC2 loss on vestibular function.
• To evaluate the efficacy of TMC1 gene replacement therapy.

Main Methods:

• Quantitative polymerase chain reaction (qPCR) and fluorescence in situ hybridization - hairpin chain reaction (FISH-HCR).
• Immunostaining, FM1-43 uptake assays, and measurement of vestibular evoked potentials (VsEPs) and vestibular ocular reflexes (VORs).
• Analysis of Tmc1 knockout (KO) and Tmc2 KO mouse models.

Main Results:

• TMC1 and TMC2 exhibit dynamic developmental changes and distinct regional expression patterns in the utricle and saccule.
• Tmc1 KO mice showed a loss of VsEPs and VORs, while Tmc2 KO mice retained VsEPs.
• Neonatal Tmc1 gene replacement therapy restored VsEPs in Tmc1 KO mice for up to six months.

Conclusions:

• TMC1 and TMC2 play critical, distinct roles in vestibular mechanotransduction.
• TMC1 is essential for vestibular-evoked potentials and vestibular ocular reflexes.
• TMC1 gene replacement therapy offers a potential therapeutic strategy for vestibular dysfunction.