Journal Club: Auditory nerve characteristics change to compensate for synapse loss?

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Today's journal article

Diuba A, Gratias P, Jeffers PWC, Nouvian R, Puel JL, Kujawa SG, Bourien J. Phenotypic changes of auditory nerve fibers after excitotoxicity. 

Why I picked this article

Many people struggle to hear in noise, even when the audiogram looks normal. This is called hidden hearing loss, and has been suggested to result from loss of synapses between sensory hair cells (in particular, inner hair cells) and auditory neurons in the cochlea. "Cochlear excitotoxicity" is neurotransmitter overload, causing overstimulation at those synapses and ultimately damaging these synapses. Excitotoxicity is a well-recognised mechanism of cochlear synapse loss. However, we don't know fully how different levels of over-stimulation sometimes cause severe synapse loss, while other times it can recover without causing a measurable impact on auditory nerve transmission. The reason for this observation is not known. 

This study revisited that question using a well-controlled excitotoxicity model to see if a certain population of auditory nerves can adapt to synapse loss by changing their behaviour enough to restore / maintain auditory function. 

Some of the research findings

Models:
  • Young adult Mongolian gerbils (3-4 months old, female) 
  • Artificial perilymph (vehicle for drugs. 137NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 1 NaHCO3, and 11 glucose; pH 7.4, osmolarity, 304 ± 4.3 mosmol/L)
  • Excitotoxicity: Kainate solution (25mM in artificial perilymph) was applied to the round window niche for 60 minutes. 
From part of Fig1C. Hair cell (ihc) and surround region, with control and excitotoxicity Diuba et al. 2025

Short-term change:
  • Within 10-20 minutes after infusion of Kainate, the auditory response (as measured by compound action potential) dropped in the high-frequency zone, and remained low at the 30-minute time point after 60 minutes of perfusion. This was consistent with microscopy analysis showing swelling of region under sensory hair cells where synapses are. 
Long-term recovery:
  • Threshold of nerve activity measured by compound action potential recovered within 14 days at a variable rate depending on the frequency (τ values 1.5 - 4.8 days).
  • The amplitude of nerve activity took a lot longer to return to normal (τ values 16.0 days at 16kHz compared to 99.8 d at 2kHz) 
  • Synapse loss did not fully recover even after 20 weeks (approx. 50%) despite response recovery as above.
Low spontaneous rate nerve vs Med/high spontaneous rate nerve:
  • In recovered cochleae, fibre distribution shifted: high-spontaneous-rate fibres dominated the apical region, and basal low-SR fibres adopted firing patterns similar to control high-SR fibres. 
  • This “phenotypic convergence” may underlie functional restoration despite incomplete structural repair.
  • The findings suggest that auditory nerve fibres can compensate after excitotoxic injury by altering intrinsic response properties.
  • Implication: hyperresponsiveness observed in surviving fibres could contribute to central hyperactivity, possibly linking peripheral recovery to tinnitus-like states.

Haruna's takeaway

This is a very cool publication. The research results provide some background physiological mechanism to the idea that some subpopulation of auditory nerves is more vulnerable to noise-induced detrimental effects and pathophysiology of hidden hearing loss.  I think this publication would be a very good one to use for some synapse and auditory nerve lectures. 

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This is Haruna's 58/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.