Our ongoing project focuses on neurotrophic factor signalling that regulates the function of the feedforward (cochlea-to-brainstem) and feedback (brainstem-to-cochlea) neural pathways, and how loud sounds regulate this signalling. With this research we aim to find out how to preserve ribbon synapses in the cochlea and how to promote the recovery of hearing following noise exposure.
Work in the field has shown that the ribbon synapses between inner hair cells and spiral ganglion neurons are vulnerable to loud sounds and the effects of ageing, hampering temporal sound processing and in humans probably contributing to difficulties in speech understanding in background noise. In a recent paper (Lankinen et al. Neurobiol Aging, 2025), we showed in mouse models of accelerated hearing loss that inner hair cell synaptopathy co-exists with outer hair cell loss and that the likely upstream mechanism is the malfunction of the hair cell’s mechanotransduction apparatus, the stereocilia bundle. We also showed that long-term delivery of the bile acid tauroursodeoxycholic acid (TUDCA) mitigates progressive synapse loss, this being one of the first interventions shown to antagonize auditory synaptopathy.
In this project (Ikäheimo, Leinonen et al. J Physiol, 2024), we developed a novel imaging method for the cochlear tissue, expansion microscopy, allowing nanoscale imaging of our specimens with a conventional microscope. We studied the molecular anatomy of the hair cell’s stereocilia bundle, focusing on the progressive deterioration of its structure and function along ageing. Understanding these mechanisms will probably benefit the development of interventions to promote the maintenance of hair bundle integrity or even reverse bundle pathology, thereby promoting hearing health.
In the papers by Herranen et al. Cell Death Dis, 2020 and Ikäheimo et al. Life Sci Allience, 2021, we present MANF (Mesencephalic astrocyte-derived neurotrophic factor), encoding a proteostasis regulator, as a novel gene associated with hearing function, and ER stress as a pathophysiological mechanism driving hearing loss. We demonstrated how MANF depletion causes severe hearing loss both in mouse models and humans. Mechanistically, we showed that MANF is required for the maintenance of hair cell’s synapses and for the normal structure and function of the hair cell's stereocilia bundle.
Videos from Ikäheimo, Leinonen et al. 2024