The Auditory Electrophysiological Evaluation And Gene Therapy On The Noise-induced Cochlear Synaptopathy

Objective: The aim of this study was to explore the noise-induced cochlear synaptopathy and its evaluation,especially the sensitivity of evaluation indicator,and the relationship between noise exposure and auditory coding-in-noise deficit.The study also explored the protective effect of the recombinant adeno-associated virus(rAAV)meditated neurotrophin-3(NT-3)overexpression in cochleae against the noise-induced damage to the synapses between inner hair cells(IHCs)and type-I afferent terminals.Methods: The guinea pigs were exposed to noise at the level of 106 dB SPL for 2 hours.1 month after exposure,they were compared with normal individuals by near-field recorded compound action potential(CAP)and forward masking recovery functions,and near-and far-field recorded AM responses at the level of 80 dB SPL.Meanwhile,the modulation amplitude was measured under a masking noise.After the physiological tests,the animals were sacrificed for synapses count in the high-frequency region.The effect sizes(Hedge's g method)of all tests were calculated,to compare their sensitivity for detection of synaptopathy.Moreover,the difference of masking effects on modulation amplitude by masking noise between groups was compared,to explore the relationship of noise exposure and auditory coding-in-noise deficit.One week before noise exposure,the rAAV-NT-3 was delivered into one side of animals' cochleae via cochleostomy,and the other side was injected with normal saline as the self-control.Then the animals were exposed to a 105 dB SPL noise.Two weeks after exposure,near-field recorded AM responses from both sides were compared,and compared with the one from no noise exposed individuals.After physiological tests,the animals were sacrificed for synapses count,to evaluate the protection of rAAV-NT-3 transfection.Results: Compared with the control group,the exposed group had significant decreased synapse densities at 8,16 and 32 k Hz,with the densities deceased by about 10%.Compared with the control group,the exposed group had significant decreases in forward masking recovery function at 16 k Hz,near-field recorded AM response at 8,16 and 32 k Hz,and far-field recorded AM response at 32 k Hz.The size effect of the near-field recorded AM response was no less than others.The masking effect on AM response of exposed group by masking noise was no higher than the control group.Two weeks after noise exposure,the near-field recorded AM response of the NT-3 overexpressed group,was significantly higher than the normal saline group,but no less than the no-noise control group.The synapse densities of the NT-3 overexpressed group and normal saline group were significant lower than the no-noise control,however,the densities of the NT-3 overexpressed group were higher than the normal saline group at the frequency of 11.3,16,and 22.3k Hz.NT-3 overexpression appeared to reduce the noise-induced synapse loss by ~38.5% at 8-32 k Hz.Conclusion: 106 dB SPL noise exposure caused a noise-induced cochlear synaptopathy.Near-field recorded AM response at high levels was more sensitive to detection of noise-induced cochlear synaptopathy,but not proved the relationship between noise exposure and auditory coding-in-noise deficit.The rAAV mediated overexpression of NT-3 in IHCs of basal turn,partially protected the cochleae against noise-induced synaptopathy.