Ribbon synapses of cochlear inner hair cells (IHCs) undergo molecular assembly and extensive functional and structural maturation before hearing onset. Here, we characterized the nanostructure of IHC synapses from late prenatal mouse embryo stages (embryonic days 14-18) into adulthood [postnatal day (P)48] using electron microscopy and tomography as well as optical nanoscopy of apical turn organs of Corti. We find that synaptic ribbon precursors arrive at presynaptic active zones (AZs) after afferent contacts have been established. These ribbon precursors contain the proteins RIBEYE and piccolino, tether synaptic vesicles and their delivery likely involves active, microtubule-based transport pathways. Synaptic contacts undergo a maturational transformation from multiple small to one single, large AZ. This maturation is characterized by the fusion of ribbon precursors with membraneanchored ribbons that also appear to fuse with each other. Such fusion events are most frequently encountered around P12 and hence, coincide with hearing onset in mice. Thus, these events likely underlie the morphological and functional maturation of the AZ. Moreover, the postsynaptic densities appear to undergo a similar refinement alongside presynaptic maturation. Blockwise addition of ribbon material by fusion as found during AZ maturation might represent a general mechanism for modulating ribbon size. synaptogenesis | presynaptic development | ribbon synapse maturation | synaptic heterogeneity I n mammals, synaptic sound encoding occurs at the first auditory synapse between cochlear inner hair cells (IHCs) and postsynaptic neurites of afferent spiral ganglion neurons (SGNs). The highly specialized IHC presynaptic active zones (AZs) are characterized by the presence of proteinaceous electron-dense bodies, called "synaptic ribbons," which are primarily composed of the structural cytomatrix protein RIBEYE (1, 2). Ribbons provide presynaptic scaffolding, cluster and functionally regulate presynaptic Ca 2+ channels at the AZ membrane (3-5), and tether a halo of synaptic vesicles (SVs) (6). This latter feature is thought to enable rapid and indefatigable vesicular replenishment to the release site-even during periods of persistent stimulation (3,5,7,8).In mice, hearing onset occurs around postnatal day (P)12 (9) before which, IHC presynaptic AZs undergo a range of structural and functional refinements. For example, extrasynaptically localized Ca 2+ channels are progressively eliminated from the nonsynaptic basolateral plasma membrane and form-in concert with the corresponding postsynaptic glutamate receptor patchestightly confined clusters at mature presynaptic AZs (3, 10). Moreover, otoferlin-a large Ca 2+ -binding multi-C 2 domain protein (11, 12)-likely replaces synaptotagmins as the putative Ca 2+ sensor of IHC release during the first postnatal week (13). This finding reflects a key landmark of functional maturation of this unconventional high-throughput release machinery and is essentially required to faithfully orchestrate vesicular...

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Pneumonia outbreak in the city of Wuhan, China, prompted the finding of a novel strain of severe acute respiratory syndrome virus (SARS-CoV-2). Here, we discuss potential long-term consequences of SARS-CoV-2 infection, and its possibility to cause permanent damage to the immune system and the central nervous system. Advanced chronological age is one of the main risk factors for the adverse outcomes of COVID-19, presumably due to immunosenescence and chronic low-grade inflammation, both characteristic of the elderly. The combination of viral infection and chronic inflammation in advanced chronological age might cause multiple detrimental unforeseen consequences for the predisposition and severity of neurodegenerative diseases and needs to be considered so that we can be prepared to deal with future outcomes of the ongoing pandemic.