J Neurosci. 2016 Sep 28;36(39):10214-27. doi: 10.1523/JNEUROSCI.0226-16.2016.

Conductive Hearing Loss Has Long-Lasting Structural and Molecular Effects on Presynaptic and Postsynaptic Structures of Auditory Nerve Synapses in the Cochlear Nucleus.

Clarkson C1, Antunes FM1, Rubio ME2.
1 Departments of Otolaryngology and.
2 Departments of Otolaryngology and Neurobiology and Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 mer@pitt.edu.


Sound deprivation by conductive hearing loss increases hearing thresholds, but little is known about the response of the auditory brainstem during and after conductive hearing loss. Here, we show in young adult rats that 10 d of monaural conductive hearing loss (i.e., earplugging) leads to hearing deficits that persist after sound levels are restored. Hearing thresholds in response to clicks and frequencies higher than 8 kHz remain increased after a 10 d recovery period. Neural output from the cochlear nucleus measured at 10 dB above threshold is reduced and followed by an overcompensation at the level of the lateral lemniscus. We assessed whether structural and molecular substrates at auditory nerve (endbulb of Held) synapses in the cochlear nucleus could explain these long-lasting changes in hearing processing. During earplugging, vGluT1 expression in the presynaptic terminal decreased and synaptic vesicles were smaller. Together, there was an increase in postsynaptic density (PSD) thickness and an upregulation of GluA3 AMPA receptor subunits on bushy cells. After earplug removal and a 10 d recovery period, the density of synaptic vesicles increased, vesicles were also larger, and the PSD of endbulb synapses was larger and thicker. The upregulation of the GluA3 AMPAR subunit observed during earplugging was maintained after the recovery period. This suggests that GluA3 plays a role in plasticity in the cochlear nucleus. Our study demonstrates that sound deprivation has long-lasting alterations on structural and molecular presynaptic and postsynaptic components at the level of the first auditory nerve synapse in the auditory brainstem.


Despite being the second most prevalent form of hearing loss, conductive hearing loss and its effects on central synapses have received relatively little attention. Here, we show that 10 d of monaural conductive hearing loss leads to an increase in hearing thresholds, to an increased central gain upstream of the cochlear nucleus at the level of the lateral lemniscus, and to long-lasting presynaptic and postsynaptic structural and molecular effects at the endbulb of the Held synapse. Knowledge of the structural and molecular changes associated with decreased sensory experience, along with their potential reversibility, is important for the treatment of hearing deficits, such as hyperacusis and chronic otitis media with effusion, which is prevalent in young children with language acquisition or educational disabilities.



Supplemental material

Sound reduction by conductive hearing loss is known to alter the neuronal metabolic rates and protein synthesis in the brainstem (1, 2). However, despite being the second most prevalent form of hearing loss, conductive hearing loss and its effects on central synapses have received relatively little attention. Transient conductive hearing loss for one day led to a reversible increase in hearing thresholds and to reversible synaptic up-regulation of GluA3 subunits of the AMPA type of glutamate receptors at auditory nerve synapses in the ventral cochlear nucleus. The same neurons showed a down regulation of glycine receptor a1 subunit on inhibitory synapses that reversed once hearing levels were restored (3), suggesting the existence of a homeostatic response to the reduced sound. On contrary, our recent study showed that a longer period of transient conductive hearing loss leads to significant changes in the brain that outlast the period of hearing loss. In these experiments, mature rats temporarily received an ear plug for 10 days and were tested again 10 days after ear plug removal. Even after 10 days of return to normal hearing, these animals had elevated hearing thresholds and an increase in central gain upstream of the cochlear nucleus perhaps indicating hyperacusis. On a structural level, synapses in the cochlear nucleus had structural and molecular abnormalities. These findings are quite novel, because it shows that the subcortical auditory system remains highly plastic even in adult animals, correcting the commonly accepted view that it is not.

Our study also raises awareness that even mild and temporary conducting hearing loss in humans, often seen as benign, may have long-lasting detrimental effects. Many people can deal with a bit of hearing loss and it does not affect their daily life very much, but it does have serious consequences in the long term. If your hearing loss accelerates it can prevent you from interacting socially (4). Future studies could investigate in the adult, long-term hearing sensitivities following conductive hearing loss in chronic otitis media with effusion, which is prevalent in children. Such studies will settle the central mechanisms of deficits in auditory perception, language acquisition or educational disabilities that occur after inadequate or abnormal sensory experience.

Current literature about hearing loss show that there are multiple ways through which neurons in the central nervous system respond to fluctuations in their inputs and that probably these responses relate to the etiology of hearing loss. For these reasons, more studies are needed to underpin the cellular mechanisms as well as determining common features that will help us to understand whether the reported synaptic modifications compensate for the hearing deficits or represent pathological responses to hearing loss.


Figure 1. Cartoon summary of the data obtained in this study. A. Traces of auditory brainstem recordings at 80 dB SPL in normal hearing, at 10 days of ear plugging and after 10 days of ear plugged removal. I: auditory nerve; II: cochlear nucleus; III: superior olivary complex. B. Summary of structural and molecular changes at auditory nerve synapses in response to 10 days of transient conductive hearing loss (ear plugging). After 10 days of ear plugging, there was a decrease in vesicular glutamate transporter 1 (vGluT1) labeling at auditory nerve endings and in the size of synaptic vesicles (SVs). Post-synaptically, the postsynaptic densities (PSDs) of the auditory nerve on bushy cells somata were thicker and contained increased GluA3 AMPAR subunits. Ten days after earplug removal, there was an increase in the density of SVs in the auditory nerve; SVs were also larger in size. On BCs, the PSD apposed to the AN were larger and thicker, and they contained fewer GluA2 but more GluA3 subunits.



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