Thirumalini Vaithianathan

Biography

I have devoted my career to understanding how changes in single synapse function affect the computational properties of the synapse, particularly in a disease model of retinal neuropathy. Understanding the function of single synapse in depth requires knowledge about vesicle dynamics combining calcium signals that control the rate of release and recycling, as well the functional roles of the synaptic proteins that participate in stimulus-evoked responses. To achieve this goal, we first need to determine the dynamics of single synaptic neurotransmitter-releasing vesicles in living neurons, and thus track the events that occur before, during, and after neurotransmitter release. I began to successfully accomplish this research goal during my postdoctoral training in retinal ribbon synapses, a specialized and functionally critical organelle at the active zone of sensory synapses in the retina. Ribbon synapses supply release-ready synaptic vesicles to support neurotransmission. Now, my direct approach to imaging single vesicles revealed for the first time the dynamics of this supply process at living synapses. To do so, I used super-resolution photoactivated localization microscopy and pHluorin-based reporters to track single synaptic vesicles at the active zone of voltage-clamped sensory synapses before and during transmitter release. Thus, I was also able to resolve Ca2+ nanodomains--calcium in neurotransmitter release--at the active zone with millisecond precision. As a postdoctoral researcher, I also began to make significant advances in the molecular front, i.e., a molecular dissection of ribbon synapse function in mouse and zebrafish retina. Indeed, I analyzed the functional roles of proteins associated with ribbon structure, the CtBP1 (C-terminal binding protein 1), and the proteins that bind to the molecular machinery for synaptic vesicle fusion (the SNARE complex), the complexins. I showed that the absence of CtBP1 did not affect the formation or function of retinal ribbon synapses and demonstrated a dual role for complexin in stabilizing SNARE complexes at ribbons and preventing fusion in the absence of Ca2+ influx, while also facilitating SNARE-mediated fusion during Ca2+ influx.