A mouse model of neurofibromatosis type 2 to investigate sensorineural hearing loss associated with vestibular schwannomas

Background Neurofibromatosis type 2 (NF2) is associated with loss of NF2/Merlin, which leads to schwannomas of the vestibular nerve and varying degrees of sensorineural hearing loss (SNHL). The etiology of the hearing loss remains to be elucidated, although leading current theories implicate the secretion of pro-inflammatory and potentially neurotoxic factors. In this study, we examined the auditory and vestibular nerves in a mouse model for NF2 to further investigate the underlying cochlear NF2 phenotype.

Methods NF2 mice or controls were aged up to 11 months. Animals underwent serial measurements of auditory brainstem responses (ABR) and 5-Ethynyl-2′-deoxyuridine (EdU) injections. Inner ear histology was performed for glial and neuronal markers at 11 months. Proliferation was assessed after EdU labeling. Schwann cells and neurons were quantified on serial sections. Cochlear whole mounts were stained and quantified for synaptic markers. Glial cells at early and late time points were isolated using fluorescence-activated cell sorting (FACS), and microRNA and mRNA were isolated for quantitative PCR.

Results At 10-11 months of age, and compared to controls, ABR demonstrated significant hearing loss in all NF2 animals. EdU increased proliferation of glial cells within the cochlea that was associated with increased loss of ribbon synapses, followed by neuronal loss.

Conclusions NF2 mice display a cochlear phenotype that associated with dysregulation of glial cell proliferation after loss of NF2/Merlin. This proliferation is further associated with a loss of auditory synapses and neurons. These findings may in part explain the sensorineural hearing loss in patients with vestibular schwannomas.

Publication History

Article published online:
12 May 2023