Kv4, Kv2, and Kv3 currents shape intrinsic lateral olivocochlear excitability independent of hair cell dysfunction during development and ageing.

Abstract

Intrinsic lateral olivocochlear (iLOC) neurons provide vital brainstem efferent feedback to the cochlea in order to modulate hearing sensitivity through synapses onto type-I spiral ganglion neurons. During ageing or mutations affecting hair cell transduction in mice, efferent neurons rewire to form direct axo-somatic synapses onto inner hair cells (IHCs), recapitulating a synaptic configuration typically only restricted to the immature cochlea. Whether this rewiring reflects a compensatory mechanism or some form of attempted repair, or how iLOC biophysics change throughout ageing and this rewiring process, is not known. We utilised whole-cell patch-clamp electrophysiology to investigate iLOC activity and their underlying biophysics across the wild-type mouse lifespan. We show that iLOC neurons undergo a progressive increase in excitability with post-natal development and ageing, producing more spikes for a given stimulus. This intrinsic excitability shift was driven by the developmental decline in the A-type Kv4 mediated potassium current and increase in Kv2 mediated current. In ageing animals, and distinct from post-natal development, further increased firing rates were supported by an increased size of the fast-activating Kv3 current. Spontaneous bursting activity remained present in ageing iLOC neurons, and no reversion to an immature biophysics profile was evident. Interestingly, despite robustly eliciting efferent rewiring of IHCs, an accelerated ageing-like re-innervation genetic model did not recreate the biophysical changes in the iLOC neurons that reflected the ageing system. This work reveals distinct processes occurring within the iLOC feedback system, and shows that age-related enhancements of SGN resting activity are not triggered by deficits in IHC transduction. Significance StatementModulation of cochlea output from the brainstem remains poorly understood, and the efferent feedback from the intrinsic lateral olivocochlear (iLOC) neurons has been shown to be vital for maintaining hearing sensitivity after noise exposure. Efferent neurons undergo significant rewiring within the cochlea during maturation that appears to revert to an immature state with ageing or with dysfunction of the inner hair cell sound-transducing apparatus, though how iLOC activity adapts to this is unknown. Here we show that ageing involves distinct shifts in sodium and potassium current biophysics that support the generation and development of spontaneous bursting activity. Disrupting sound transduction revealed that iLOC age-related biophysical changes and cochlear rewiring are independent, and defective transduction is insufficient to recreate ageing biophysics.