Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells.
Inner hair cell ribbon synapses indefatigably transmit acoustic information. The proteins mediating their fast vesicle replenishment (hundreds of vesicles per s) are unknown. We found that an aspartate to glycine substitution in the C(2)F domain of the synaptic vesicle protein otoferlin impaired hearing by reducing vesicle replenishment in the pachanga mouse model of human deafness DFNB9. In vitro estimates of vesicle docking, the readily releasable vesicle pool (RRP), Ca(2+) signaling and vesicle fusion were normal. Moreover, we observed postsynaptic excitatory currents of variable size and spike generation. However, mutant active zones replenished vesicles at lower rates than wild-type ones and sound-evoked spiking in auditory neurons was sparse and only partially improved during longer interstimulus intervals. We conclude that replenishment does not match the release of vesicles at mutant active zones in vivo and a sufficient standing RRP therefore cannot be maintained. We propose that otoferlin is involved in replenishing synaptic vesicles.
Pangrsic
Tina
T
InnerEarLab, Department of Otolaryngology and Center for Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.
Lasarow
Livia
L
Reuter
Kirsten
K
Takago
Hideki
H
Schwander
Martin
M
Riedel
Dietmar
D
Frank
Thomas
T
Tarantino
Lisa M
LM
Bailey
Janice S
JS
Strenzke
Nicola
N
Brose
Nils
N
Müller
Ulrich
U
Reisinger
Ellen
E
Moser
Tobias
T
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D003638:Deafness / Q000378:metabolism*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism* / Q000648:ultrastructure; D006309:Hearing / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants; D020125:Mutation, Missense; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
D008565:Membrane Proteins; C516233:otoferlin protein, mouse