Impaired mechanoelectrical transduction drives efferent re-innervation of inner hair cells

The inner hair cells (IHCs) are the primary sensory cells within the mammalian cochlea and are responsible for detecting acoustic stimuli and converting them into electrical signals for the brain to perceive sound. This conversion is performed by the mechanoelectrical transducer (MET) channels that are found on the stereocilia atop IHCs. During postnatal development IHCs receive transient axosomatic (direct) innervation by the efferent fibres which is then lost after the onset of hearing, which in mice is around postnatal day 12. Studies have shown that IHCs become re-innervated by efferent fibres in ageing mice and in mouse models with impaired MET channel function (Myo7afl/fl;Myo15 cre+/-). However, the details of how this mechanism takes place remain unclear. It is currently unknown whether the re-innervation of the IHCs occurs as a consequence of general cellular dysfunction or if it is specific to impaired MET function.
Experiments were performed using Myo7afl/fl;Myo15 cre+/- mice, and from two additional conditional knockout (cKO) mouse models that specifically disrupted neurotransmitter release in IHCs, whilst maintaining MET functionality (Otoferlintm1c;Vglut3 cre-ERT2 and Otoffl/fl;Myo15 cre+/-). Myo7a encodes for the unconventional myosin 7a, which is required for MET function, while Otof encodes for the Ca2+ sensor of neurotransmitter release otoferlin. Immunofluorescence was used to determine the expression profile of the pre- and post-synaptic proteins of the efferent system. Ex vivo whole cell patch-clamp electrophysiology was used to identify the function of the re-innervating efferent system.
The results show that IHCs from Myo7afl/fl Myo15 cre+/- mice were re-innervated by the efferent fibres from about P24 onwards. Prior to the efferent re-innervation, the IHCs re-express post-synaptic small conductance Ca2+ activated potassium channels (SK2) but IHCs do not show functional efferent synapses until P25. This indicates the IHCs drive the efferent re-innervation. Conversely to the recent literature, the IHCs lose their afferent synapses after the re-innervation of IHCs. In both otoferlin cKO mice, there was no visible return of axosomatic efferent innervation on IHCs, indicating that the re-innervation is likely to be driven by impaired mechanoelectrical transduction.