AP180 promotes release site clearance and clathrin-dependent vesicle reformation in mouse cochlear inner hair cells

Author:

Kroll Jana1234ORCID,Özçete Özge Demet3456,Jung Sangyong57,Maritzen Tanja8ORCID,Milosevic Ira13ORCID,Wichmann Carolin235ORCID,Moser Tobias35689ORCID

Affiliation:

1. Synaptic Vesicle Dynamics Group, European Neuroscience Institute Göttingen – A Joint Initiative of the University Medical Center Göttingen and the Max-Planck-Society, Göttingen, Germany

2. Molecular Architecture of Synapses Group, Institute for Auditory Neuroscience, InnerEarLab and Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany

3. Collaborative Research Center 889, University of Göttingen, Göttingen, Germany

4. Göttingen Graduate School for Neuroscience and Molecular Biosciences, University of Göttingen, Göttingen, Germany

5. Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany

6. Auditory Neuroscience Group, Max Planck Institute of Experimental Medicine, Göttingen, Germany

7. Neuro Modulation and Neuro Circuitry Group, Singapore Bioimaging Consortium (SBIC), Biomedical Sciences Institutes, 138667 Singapore

8. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany

9. Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Abstract

High-throughput neurotransmission at ribbon synapses of cochlear inner hair cells (IHCs) requires tight coupling of neurotransmitter release and balanced recycling of synaptic vesicles (SVs) as well as rapid restoration of release sites. Here, we examined the role of the adaptor protein AP180 for IHC synaptic transmission in AP180-KO mice using high-pressure freezing and electron tomography, confocal microscopy, patch-clamp membrane-capacitance measurements and systems physiology. AP180 was found predominantly at the synaptic pole of IHCs. AP180-deficient IHCs had severely reduced SV numbers, slowed endocytic membrane retrieval, and accumulated endocytic intermediates near ribbon synapses, indicating that AP180 is required for clathrin-dependent endocytosis and SV reformation in IHCs. Moreover, AP180 deletion led to a high prevalence of SVs in a multi-tethered or docked state after stimulation, a reduced rate of SV replenishment, and a hearing impairment. We conclude that, in addition to its role in clathrin recruitment, AP180 contributes to release site clearance in IHCs.

Funder

Deutsche Forschungsgemeinschaft

Publisher

The Company of Biologists

Subject

Cell Biology

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