Biology subjects

Rankovic, V.

Publications and source records attributed to Rankovic, V..

3 recordsLinked to original sources

bioRxiv2025

Developmental plasticity facilitates the structural maturation of cochlear inner hair cell ribbon synapses

Sound detection occurs in the cochlea, where sensory inner hair cells (IHC) accurately convert auditory stimuli into neurochemical signals. Presynaptically, IHCs harbor synaptic ribbons, specialized scaffolds that facilitate ultrafast and indefatigable exocytosis. During synapse assembly and subsequent maturation, IHC ribbons increase in volume and synaptic vesicle tethering capacity. This development is thought to result from progressive precursor aggregation. However, the underlying mechanisms of ribbon synapse formation have remained elusive thus far. In this study, we established a novel triple-color live-cell imaging approach to monitor IHC pre-synaptogenesis in situ. We found that ribbon precursors are highly dynamic and undergo bidirectional plasticity. The presynaptic active zone (AZ) forms a focal point for dramatic structural remodeling of precursors, which the AZ recruits, confines and redistributes. Furthermore, silencing spontaneous synaptic activity decreased precursor mobility and plasticity at the AZ. This suggests a fundamental role for activity-dependent Ca2+ influx in the plastic development shaping the unique properties of auditory ribbon synapses.

neuroscience↗

bioRxiv2024

Slow kinesin-dependent microtubular transport facilitates ribbon synapse assembly in developing cochlear inner hair cells

Sensory synapses are characterized by electron-dense presynaptic specializations, so-called synaptic ribbons. In cochlear inner hair cells (IHCs), ribbons play an essential role as core active zone (AZ) organizers, where they tether synaptic vesicles, cluster calcium channels and facilitate the temporally-precise release of primed vesicles. While a multitude of studies aimed to elucidate the molecular composition and function of IHC ribbon synapses, the developmental formation of these signalling complexes remains largely elusive to date. To address this shortcoming, we performed long-term live-cell imaging of fluorescently-labelled ribbon precursors in young postnatal IHCs to track ribbon precursor motion. We show that ribbon precursors utilize the apico-basal microtubular (MT) cytoskeleton for targeted trafficking to the presynapse, in a process reminiscent of slow axonal transport in neurons. During translocation, precursor volume regulation is achieved by highly dynamic structural plasticity - characterized by regularly-occurring fusion and fission events. Pharmacological MT destabilization negatively impacted on precursor translocation and attenuated structural plasticity, whereas genetic disruption of the anterograde molecular motor Kif1a impaired ribbon volume accumulation during developmental maturation. Combined, our data thus indicate an essential role of the MT cytoskeleton and Kif1a in adequate ribbon synapse formation and structural maintenance.

neuroscience↗

bioRxiv2023

CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells

To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.

neuroscience↗