Effects of Wbp2 gene activation and the modifier Cdh23^ahl on progressive hearing loss in Wbp2 mouse mutants

Synapses are thought to be a vulnerable site in hearing loss. One gene required for normal synapse maintenance is Wbp2, which encodes a transcriptional co-activator of oestrogen and progesterone receptors. The Wbp2^tm2a mouse mutant allele knocks down transcription to minimal levels and leads to progressive increase in ABR thresholds for high frequencies from 4 weeks onwards in homozygotes. This is accompanied by swelling of nerve terminals below inner hair cells and dysregulation of key post-synaptic proteins. We have used the design of the Wbp2^tm2a mutation to investigate whether the synaptic swelling and increase in auditory thresholds can be prevented or reversed by activating the Wbp2 gene either prior to or after the onset of hearing loss, respectively. The influence of a common modifier of auditory function, Cdh23^ahl, was also studied by crossing a repaired Cdh23 allele into the Wbp2^tm2a colony. We found that activation of Wbp2 at either 4 weeks old or postnatal day 4 failed to halt or prevent the progression of hearing loss in Wbp2^tm2a homozygous mutant mice. Surprisingly, correction of the Cdh23^ahl allele in Wbp2^tm2a/tm2a mice completely abolished the auditory phenotype, restoring hearing thresholds to normal up to 26 weeks of age. These findings reveal the difficulty in reversing early-onset synaptic defects and highlight genetic background, including known modifiers like Cdh23^ahl, as a critical factor in auditory research.