During synaptic transmission, exocytosis and endocytosis of synaptic vesicles must be balanced for maintaining the number of releasable vesicles. We found that protein kinase G (PKG) plays this balancing role at the calyx of Held presynaptic terminals when glutamate is massively released by exocytosis. Glutamate increases postsynaptic NO via Ca
2+ influx through NMDA receptors, and NO retrogradely activates PKG. PKG activates RhoA/Rho-kinase, thereby elevating the PIP
2 level that is critical for clathrin-mediated endocytosis. When this feedback cascade was inhibited, fidelity of neurotransmission was disrupted. We conclude that the exo-endocytic vesicle coupling supports high-fidelity high-frequency transmission at the fast central synapse.
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