With the development of neural prostheses, neural plasticity including synaptic remodeling under electrical stimulation is drawing more and more attention. Indeed, intracochlear electrical stimulation used to restore hearing in deaf can induce the loss of residual hearing and synapses of the inner hair cells (IHCs). However, the mechanism under this process is largely unknown. Considering that the guinea pig is always a suitable and convenient choice for the animal model of cochlea implant (CI), in the present study, normal-hearing guinea pigs were implanted with CIs. Four-hour electrical stimulation with the intensity of 6 dB above electrically evoked compound action potential (ECAP) threshold (which can decrease the quantity of IHC synapses and the excitability of the auditory nerve) resulted in the upregulation of Bdnf (p < 0.0001) and downregulation of Nt-3 (p < 0.05). Intracochlear perfusion of exogenous NT-3 or TrkC/Fc (which blocks NT-3) can, respectively, resist or aggravate the synaptic loss induced by electrical stimulation. In contrast, local delivery of exogenous BDNF or TrkB/Fc (which blocks BDNF) to the cochlea, respectively, exacerbated or protected against the synaptic loss caused by electrical stimulation. Notably, the synaptic changes were only observed in the basal and middle halves of the cochlea. All the findings above suggested that NT-3 and BDNF may play opposite roles in the remodeling of IHC synapses induced by intracochlear electrical stimulation, i.e. NT-3 and BDNF promoted the regeneration and degeneration of IHC synapses, respectively.
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We thank Professor Zhengmin Wang of our department for critical comments and suggestions on our research work. We are grateful to Z. SUN, C. Xu and W. Fan (Shanghai Listent Medical Technology Co., LTD.) for technical support of ECAP measurement and analysis. We further thank Shanghai Listent Medical Technology Co., LTD. for providing customized electrode arrays and pulse generators.
This work was supported by the grants from National Natural Science Foundation of China (No. 81670927).
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The original version of this article was revised: Figure 9 has been corrected.
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Supplementary file1 (JPG 985 kb) Supplemental Fig. 1. The quantity of presynaptic ribbons (a, c) and postsynaptic patches (b, d) following intracochlear perfusion of exogenous NT-3. (a-b) Quantity of presynaptic ribbons (a) and post synaptic patches (b) per IHC under different conditions. One-way ANOVA with post hoc Bonferroni correction or Kruskai- Wallis test with post hoc Dunn test was performed, n = 5 for each group. (c-d) Comparisons of the quantity of presynaptic ribbons (c) and post synaptic patches (d) per IHC between AP and NT-3 perfused cochlea. Two-tailed unpaired student’s t test or Mann-Whitney test was conducted, n = 5 for each group. Box represents the 25%-75% range, error bars represent the 10%-90% range, and the line and “+” within the box represent the median and mean, respectively. **** P < 0.0001.
Supplementary file2 (JPG 939 kb) Supplemental Fig. 2. The quantity of presynaptic ribbons (a, c) and postsynaptic patches (b, d) following intracochlear perfusion of TrkC/Fc. (a-b) Quantity of presynaptic ribbons (a) and postsynaptic patches (b) per IHC under different conditions. One-way ANOVA with post hoc Bonferroni correction or Kruskai- Wallis test with post hoc Dunn test was performed, n = 5 for each group. (c-d) Comparisons of the quantity of presynaptic ribbons (c) and postsynaptic patches (d) per IHC between AP- and TrkC/Fc-perfused cochlea. Two-tailed unpaired student’s t test or Mann-Whitney test was conducted, n = 5 for each group. Box represents the 25%-75% range, error bars represent the 10%-90% range, and the line and “+” within the box represent the median and mean, respectively. *** P < 0.001, **** P < 0.0001.
Supplementary file1 (JPG 1012 kb) Supplemental Figure 3. The quantity of presynaptic ribbons (a, c) and postsynaptic patches (b, d) following intracochlear perfusion of exogenous BDNF. (a-b) Quantity of presynaptic ribbons (a) and post synaptic patches (b) per IHC under different conditions. One-way ANOVA with post hoc Bonferroni correction or Kruskai- Wallis test with post hoc Dunn test was performed, n = 5 for each group. (c-d) Comparisons of the quantity of presynaptic ribbons (c) and post synaptic patches (d) per IHC between AP- and BDNF-perfused cochlea. Two-tailed unpaired student’s t test or Mann-Whitney test was conducted, n = 5 for each group. Box represents the 25%-75% range, error bars represent the 10%-90% range, and the line and “+” within the box represent the median and mean, respectively. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001.
Supplementary file1 (JPG 988 kb) Supplemental Fig. 4. The quantity of presynaptic ribbons (a, c) and postsynaptic patches (b, d) following intracochlear perfusion of TrkB/Fc. (a-b) Quantity of presynaptic ribbons (a) and post synaptic patches (b) per IHC under different conditions. One-way ANOVA with post hoc Bonferroni correction or Kruskai- Wallis test with post hoc Dunn test was performed, n = 5 for each group. (c-d) Comparisons of the quantity of presynaptic ribbons (c) and post synaptic patches (d) per IHC between AP- and TrkB/Fc-perfused cochlea. Two-tailed unpaired student’s t test or Mann-Whitney test was conducted, n = 5 for each group. Box represents the 25%-75% range, error bars represent the 10%-90% range, and the line and “+” within the box represent the median and mean, respectively. ** P < 0.01, *** P < 0.001, **** P < 0.0001.
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Li, Q., Chen, M., Zhang, C. et al. Opposite Roles of NT-3 and BDNF in Synaptic Remodeling of the Inner Ear Induced by Electrical Stimulation. Cell Mol Neurobiol (2020). https://doi.org/10.1007/s10571-020-00935-x
- Synaptic remodeling
- Electrical stimulation
- Cochlear implant (CI)
- Neurotrophin-3 (NT-3)
- Brain derived neurotrophic factor (BDNF)