Journal Club: Inhibiting autophagy maybe how neurotrophic factor protect synapses against noise-induced synaptopathy.

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Today's journal article

Wang F, Yu Q, Luo Y, Guo R, Wu L, Song X, Li Y, Li S, Liu K, Jiang X. BDNF Alleviates Noise-Induced Cochlear Synaptopathy Through Inhibition of Autophagy. 

Why I picked this article

This research investigates the relationship between autophagy and a neurotrophic factor called "Brain-derived neurotrophic factor (BDNF) in the context of protection against noise-induced hearing loss. 

Excessive noise exposure causes permanent hearing loss. Through decades of animal research, we now know that some noise exposure can cause temporary loss of hearing that results from reduced synapses, or "connections" between sensory cells and auditory neurons. Through further noise exposure, this can manifest into permanent hearing loss. Current research efforts target how to preserve synapses in the cochlea, through our understanding of how synapses are lost following excessive noise exposure. 

"Autophagy" is a process through which the cell digests and removes damaged proteins, and allows the ingredients of proteins to be recycled. It involves the formation of autophagic vesicles, or packages of old proteins to be recycled, which then fuse with the lysosome, an intracellular organelle with an acidic inside that can break down proteins. Lysosomes in a cell are like the stomach in the human body. While autophagy is presumably an important part of cell's healthy routine, too much or too little autophagy can also be damaging to cells, including cochlear cells. 

This article explores the hypothesis that BDNF, a compound known to be protective against noise-induced hearing loss, protect synapses by reducing protein degradation by autophagy. 

Some of the research findings

Animal Model:
  • C57BL/6 J mice (6 weeks old)
  • Temporary hearing loss model: Noise exposure group received white noise exposure 100 dB SPL, 2 h
  • Permanent hearing loss model: Received two doses of white noise exposure 100 dB SPL, 2 h, two weeks apart.
  • BDNF treatment: control or hearing loss model received BDNF in the left ear. 
  • Animal's hearing was assessed with the auditory brainstem response
  • Synapses in auditory sensory cells, in particular, inner hair cells, were assessed by microscopy.
  • Visualisation of synapses and autophagy-related organelles:
  • Synapse markers
    • mouse anti-CtBP2 (1:500 dilution; Abcam, ab204663)
    • mouse anti-GluR2 (1:400 dilution; Millipore, MAB397)
  • Autophagy markers 
    • LC3B - marker of autophagic vesicles: rabbit anti-LC3B (1:100 dilution; CST, 3868 T), 
    • Lamp1 - marker for lysosome: rat anti-Lamp1 (1:300 dilution; Abcam, ab25245)
Findings: 
  • Noise exposure reduces coupled synapses in the cochlea by 14 days post-noise. This was mitigated by the administration of BDNF, confirming the protective effect of BDNF against noise-induced hearing loss. 
  • To test the effect of noise exposure on autophagy, researchers visualised the amount of proteins, LC3B and Lamp1, both of which are related to autophagy. 
  • In the temporary hearing loss model, 1 day after the noise exposure, LC3B and Lamp1 both increased, and then decreased to normal levels by 14 days after the noise exposure. This suggests that the autophagy process kicked in soon after the noise exposure, and then returned to normal. 
  • In the permanent hearing loss model, autophagy level was increased very much by day 14 post-2nd noise-exposure.  Again, this was mitigated (but not entirely) by treatment with BDNF. 
  • In the cultured cochlear model, activation of autophagy by the use of rapamycin, a drug known to increase autophagy, enhanced the amount of autophagy, but again, BDNF was able to mitigate this.
  • A series of protein detection data also agrees with the idea that autophagy is suppressed by BDNF. 
Part of Figure 3b. Red colour shows the lysosome marker and blue shows the cell nucleus. More signal 1 day after noise exposure. Wang et al. (2025)

Haruna's takeaway

The connection between autophagy and synapse loss, and inhibition by a protective agent, is interesting. Organelles in auditory sensory cells are uniquely positioned within the cell because auditory sensory cells, like outer hair cells and inner hair cells, have a distinct body shape fit for their purpose, and small compartments like mitochondria and lysosomes are positioned in certain parts of the cell, particularly for outer hair cells. While the focus of this research was on the synapses on the inner hair cells, it would be interesting to compare with the outer hair cells, as the response and capability of organelles could be quite different. 

We have investigated lysosome co-localisation of P2X4 receptors, ATP-activated channels, in the past in outer hair cells. P2X4 is acid-sensitive and may be modulated by or modulating the lysosome environment. It may be interesting to get back to how exactly lysosomes work in hair cells and compare between outer vs inner hair cell.  

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This is Haruna's 32/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.