Quercetin Facilitates Vesicle Release and Inhibits Endocytosis at a Central Synapse

Quercetin has demonstrated significant potential in treating neurological diseases due to its neuroprotective effects. It has been reported to modulate neuronal excitability, thereby protecting neurons from excessive excitotoxic damage. However, the mechanisms by which quercetin modulates synaptic transmission remain elusive. In this study, we investigated the effects of quercetin on synaptic transmission using whole-cell patch-clamp techniques at the calyx of Held. We found that 100 μM quercetin increased excitatory postsynaptic currents. We also recorded presynaptic calcium currents at the giant presynaptic nerve terminal and found that quercetin did not affect calcium influx but increased the release probability of synaptic vesicles. Using whole-cell capacitance measurements, we found that quercetin significantly inhibited vesicle endocytosis without affecting exocytosis. To further address the underlying cellular mechanisms, we applied specific calmodulin inhibitors, myosin light chain kinase peptide or calmodulin binding-domain peptide in the presence of quercetin. None of the calmodulin inhibitors induced additional inhibition of endocytosis, indicating the involvement of calmodulin in quercetin-induced inhibition of endocytosis. Similarly, blocking calcineurin with calcineurin autoinhibitory peptide or cyclosporine A did not induce further inhibition of endocytosis, suggesting the involvement of calcineurin downstream of calmodulin. To explore the physiological significance of quercetin, we found that it could enhance short-term depression during repetitive stimulation. This effect was attributed to both an increase in vesicle release probability and a slowing down of endocytosis. Therefore, for the first time, we report that quercetin increases vesicle release and inhibits endocytosis via the calmodulin/calcineurin signaling pathway, providing new insights into its neuroprotective effects.