Electronic Thesis and Dissertation Repository

HEI-OC1 Cochlear Cells as an In Vitro Model to Study the Role of Connexins in Ototoxicity and Hearing Loss

Rianne Beach, The University of Western Ontario

Abstract

Connexin 26 (Cx26) and Cx30 mediate the intercellular exchange of metabolites and ions within the cochlea in a process known as gap junctional intercellular communication (GJIC). Cochlear cell death and subsequent hearing loss can arise after treatment with ototoxic therapeutics and Cx26 mutant expression. We investigated the role of connexins and GJIC in the development of ototoxicity in HEI-OC1 cochlear-derived cells. The susceptibility of HEI-OC1 cells to aminoglycoside antibiotics and cisplatin-induced cell death was not influenced by the ablation of connexins and GJIC. However, the expression of mitochondrial apoptosis or ER stress markers was altered by the degree of GJIC. Hearing loss linked Cx26 syndromic mutants (N54K and S183F) displayed diverse gain-of-function properties in HEI-OC1 cells. However, non-syndromic mutants (R32H and R184P) displayed similar loss-of-function properties. Collectively, these disease-linked Cx26 mutants exhibited three distinct cellular phenotypes, which may contribute to unique mechanisms for hearing loss in vivo.