Re: Sleep and the Family Doctor: Time to Lead

Abstract

<h3>Abstract</h3> Synaptic vesicles need to be recycled and refilled rapidly to maintain high-frequency synaptic transmission. However, little is known about the control of transport of neurotransmitter into synaptic vesicles, which determines the contents of synaptic vesicles and the strength of synaptic transmission. Here we report that Na⁺ substantially accumulated in the calyx of Held terminals of mouse during high-frequency spiking. The activity-induced elevation of cytosolic Na⁺ activated vesicular Na⁺/H⁺ exchanger, facilitated glutamate loading into synaptic vesicles and increased quantal size of asynchronous released vesicles, but did not affect the vesicle pool size or release probability. Consequently, presynaptic Na⁺ increased the excitatory postsynaptic currents and was required to maintain the reliable high-frequency signal transmission from the presynaptic calyces to the postsynaptic MNTB neurons. Blocking Na⁺/H⁺ activity with EIPA decreased the postsynaptic current and caused failures in postsynaptic firing. Therefore, during high-frequency synaptic transmission, when large amounts of glutamate are released, Na⁺ accumulated in the terminals, activated vesicular Na⁺/H⁺ exchanger, and regulated glutamate loading as a function of the level of vesicle release. <h3>Significant statement</h3> Auditory information is encoded by action potentials phase-locked to sound frequency at high rates. Large amount of synaptic vesicles are released during high-frequency synaptic transmission, accordingly, synaptic vesicles need to be recycled and refilled rapidly. We have recently found that a Na⁺/H⁺ exchanger expressed on synaptic vesicles promotes vesicle filling with glutamate. Here we showed that during high-frequency signaling, when massive vesicles are released, Na⁺ accumulates in terminals and facilitates glutamate uptake into synaptic vesicle. Na⁺ thus accelerates vesicle replenishment and sustains reliable synaptic transmission.