Enhanced hair cell postsynaptic responses alter release from presynaptic efferent neurons to prolong inhibition of the cochlea

Abstract

Gain control of the auditory system operates at multiple levels. Cholinergic medial olivocochlear (MOC) fibers that originate in the brainstem and make direct synaptic contacts at the base of the outer hair cells (OHCs) are the final targets of several feedback loops from both the periphery and higher processing cen ters. Efferent activation inhibits somatic electromotil ity of OHCs, an active amplification system within the mammalian cochlea. This is mediated by the activa tion of a calcium permeable α9α10 ionotropic cho linergic nicotinic receptor (nAChR) functionally cou pled to calcium activated SK potassium channels. The strength of cochlear inhibition is driven by the rate of MOC activity and short term facilitation at the MOC OHC synapse (Ballestero et al., 2011).The present work shows that a knockin mouse with a mutation in the α9α10 nAChR (L9’;T) with increased channel gating (Taranda et al., 2009) greatly prolongs hair cell evoked inhibitory postsynaptic currents (IPSCs). Long-term presynaptic compensatory mechanisms lead to reduced quantum content (IHC wt =1.29 ± 0.21; L9’;T= 0.83 ± 0.12, n=5- 6. OHC wt =0.23 ± 0.04, L9’;T = 0.14 ± 0.02, n=12-15). However, upon high frequency stimulation of MOC-OHC synapses, L9’;T mice exhibited more facilitation leading to greatly prolonged synaptic responses (S2 /S1- 40Hz: wt = 1.37 ± 0.16, L9’;T = 3.47 ± 0.44, n = 6-8, p< 0.05). At the cochlear physiology level, these synaptic changes were matched by a longer time course of efferent MOC suppression of DPOAEs. Thus, the maximal suppres sive effect of electrical shocks (70-s, 200 Hz) at the base of the IVth ventricle was doubled both at 16 (p < 0.01) and 22 kHz (p < 0.05), reached much more slowly (16 kHz: wt = 5.3 ± 1.0 s, L9’;T = 30.8 ± 4.1 s; 22 kHz: wt = 1.5 ± 0.4 s, L9’;T = 44.1 ± 3.1 s) and persisted for a longer time after the shocks for both 16 and 22 kHz in L9’;T mice (> 5 min) as compared to their wt littermates (≤1 s). These results indicate that the properties of the MOC-OHC synapse directly determine the efficacy of the MOC feedback to the cochlea being a main player in the “gain control” of the auditory periphery.