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Research Articles, Development/Plasticity/Repair

Macrophages Promote Repair of Inner Hair Cell Ribbon Synapses following Noise-Induced Cochlear Synaptopathy

Vijayprakash Manickam, Dinesh Y. Gawande, Andrew R. Stothert, Anna C. Clayman, Lyudmila Batalkina, Mark E. Warchol, Kevin K. Ohlemiller and Tejbeer Kaur
Journal of Neuroscience 22 March 2023, 43 (12) 2075-2089; DOI: https://doi.org/10.1523/JNEUROSCI.1273-22.2023
Vijayprakash Manickam
1Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska 68178
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Dinesh Y. Gawande
1Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska 68178
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Andrew R. Stothert
1Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska 68178
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Anna C. Clayman
2Department of Otolaryngology, School of Medicine, Washington University, St. Louis, Missouri 63110
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Lyudmila Batalkina
1Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska 68178
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Mark E. Warchol
2Department of Otolaryngology, School of Medicine, Washington University, St. Louis, Missouri 63110
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Kevin K. Ohlemiller
2Department of Otolaryngology, School of Medicine, Washington University, St. Louis, Missouri 63110
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Tejbeer Kaur
1Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska 68178
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Abstract

Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact the damaged synaptic connections after noise-induced synaptopathy. Eventually, such damaged synapses are spontaneously repaired, but the precise role of macrophages in synaptic degeneration and repair remains unknown. To address this, cochlear macrophages were eliminated using colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Sustained treatment with PLX5622 in CX3CR1GFP/+ mice of both sexes led to robust elimination of resident macrophages (∼94%) without significant adverse effects on peripheral leukocytes, cochlear function, and structure. At 1 day (d) post noise exposure of 93 or 90 dB SPL for 2 hours, the degree of hearing loss and synapse loss were comparable in the presence and absence of macrophages. At 30 d after exposure, damaged synapses appeared repaired in the presence of macrophages. However, in the absence of macrophages, such synaptic repair was significantly reduced. Remarkably, on cessation of PLX5622 treatment, macrophages repopulated the cochlea, leading to enhanced synaptic repair. Elevated auditory brainstem response thresholds and reduced auditory brainstem response Peak 1 amplitudes showed limited recovery in the absence of macrophages but recovered similarly with resident and repopulated macrophages. Cochlear neuron loss was augmented in the absence of macrophages but showed preservation with resident and repopulated macrophages after noise exposure. While the central auditory effects of PLX5622 treatment and microglia depletion remain to be investigated, these data demonstrate that macrophages do not affect synaptic degeneration but are necessary and sufficient to restore cochlear synapses and function after noise-induced synaptopathy.

SIGNIFICANCE STATEMENT The synaptic connections between cochlear inner hair cells and spiral ganglion neurons can be lost because of noise over exposure or biological aging. This loss may represent the most common causes of sensorineural hearing loss also known as hidden hearing loss. Synaptic loss results in degradation of auditory information, leading to difficulty in listening in noisy environments and other auditory perceptual disorders. We demonstrate that resident macrophages of the cochlea are necessary and sufficient to restore synapses and function following synaptopathic noise exposure. Our work reveals a novel role for innate-immune cells, such as macrophages in synaptic repair, that could be harnessed to regenerate lost ribbon synapses in noise- or age-linked cochlear synaptopathy, hidden hearing loss, and associated perceptual anomalies.

  • cochlea
  • inner hair cells
  • macrophages
  • noise-induced hearing loss
  • PLX5622
  • ribbon synapses

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The Journal of Neuroscience: 43 (12)
Journal of Neuroscience
Vol. 43, Issue 12
22 Mar 2023
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Macrophages Promote Repair of Inner Hair Cell Ribbon Synapses following Noise-Induced Cochlear Synaptopathy
Vijayprakash Manickam, Dinesh Y. Gawande, Andrew R. Stothert, Anna C. Clayman, Lyudmila Batalkina, Mark E. Warchol, Kevin K. Ohlemiller, Tejbeer Kaur
Journal of Neuroscience 22 March 2023, 43 (12) 2075-2089; DOI: 10.1523/JNEUROSCI.1273-22.2023

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Macrophages Promote Repair of Inner Hair Cell Ribbon Synapses following Noise-Induced Cochlear Synaptopathy
Vijayprakash Manickam, Dinesh Y. Gawande, Andrew R. Stothert, Anna C. Clayman, Lyudmila Batalkina, Mark E. Warchol, Kevin K. Ohlemiller, Tejbeer Kaur
Journal of Neuroscience 22 March 2023, 43 (12) 2075-2089; DOI: 10.1523/JNEUROSCI.1273-22.2023
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Keywords

  • cochlea
  • inner hair cells
  • macrophages
  • noise-induced hearing loss
  • PLX5622
  • ribbon synapses

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