Illuminating the Morphological and Functional Plasticity of the Cochlear Inner Hair Cell Ribbon SynapseCumulative thesis
Date of Examination:2023-05-16
Date of issue:2023-10-24
Advisor:Dr. Christian Vogl
Referee:Dr. Christian Vogl
Referee:Prof. Dr. Silvio Rizzoli
Referee:Prof. Dr. Jörg Enderlein
Referee:Prof. Dr. Thomas Dresbach
Referee:Dr. Brett Carter
Referee:Dr. Tina Pangrsic
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EnglishSound detection occurs in the cochlea, where sensory inner hair cells (IHC) accurately convert auditory stimuli into a neurochemical signal. Presynaptically, cochlear IHCs harbor highly-specialized electron-dense specializations – so-called ‘ribbons’ – that facilitate ultrafast, temporally-precise and indefatigable exocytosis of ribbon-tethered synaptic vesicles (SV) onto postsynaptic spiral ganglion neurons (SGN). During synapse assembly and subsequent maturation, IHC ribbons increase in volume and SV tethering capacity. This volume accumulation of the developing ribbon is thought to result from the aggregation and fusion of multiple smaller precursors at the presynaptic active zone (AZ) in a maturation process that involves plastic structural remodeling. Molecular drivers of AZ targeting and precursor aggregation however, have remained elusive thus far. Moreover, little is known of the exact processes underlying synapse assembly, nor the molecular composition of IHC ribbon precursors. In the presented studies, we established a novel method for triple-color long-term live-cell imaging of the organ of Corti in vitro and examined the plastic assembly process and mode of transport of ribbon precursors to the AZ of developing IHCs. We found that during early postnatal development, ribbon precursors are highly dynamic and subject to a period of bidirectional plasticity at the synapse. Hereby, ribbon material was not only synaptically recruited, but also disassembled and redistributed to neighboring synaptic contacts. This dramatic remodeling at and between distinct presynaptic AZs was found to depend on coordinated transport by the interwoven networks of the actin and microtubule cytoskeleton. Furthermore, inhibition of the spontaneously-generated synaptic activity in the developing organ of Corti negatively impacted ribbon precursor mobility at the AZ. This suggests a fundamental role of developmental ribbon plasticity in synaptic maturation, which may further depend on differential states of synaptic activity to shape the unique properties of mature IHC ribbon synapses.
Keywords: synaptic plasticity; cochlear inner hair cells; live-cell imaging; cytoskeleton; ribbon synapse; peripheral auditory pathway; development; spontaneous activity; synapse assembly; RIBEYE