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Abstract:
During development of the calyx of Held synapse, presynaptic action potentials (APs) become substantially faster and briefer. Nevertheless, this synapse is able to upregulate quantal output triggered by arriving APs. Briefer APs lead to less effective gating of voltage-gated Ca2+ channels (VGCCs). Therefore, mechanisms downstream of Ca2+ entry must effectively compensate for the attenuated Ca2+ influx associated with shorter APs in more mature calyces. This compensation could be achieved by tighter spatial coupling between VGCCs and synaptic vesicles, so that the latter are exposed to higher intracellular Ca2+ concentration ([Ca2+]i). Alternatively or additionally, the Ca2+ sensitivity of the release apparatus may increase during synapse development. To differentiate between these possibilities, we combined paired patch-clamp recordings with Ca2+ imaging and flash photolysis of caged Ca2+ and estimated the [Ca2+]i requirements for vesicle release in the developing mouse calyx of Held synapse. Surprisingly, the dose–response relationship between [Ca2+]i and release rate was shifted slightly to the right in more mature calyces, rendering their vesicles slightly less sensitive to incoming Ca2+. Taking into account the time course and peak rates of AP-evoked release transients for the corresponding developmental stages, we estimate the local [Ca2+]i“seen” by the Ca2+ sensors on synaptic vesicles to increase from 35 to 56 μm [from postnatal day 9 (P9)–P11 to P16–P19]. Our results reinforce the idea that developmental tightening of the spatial coupling between VGCCs and synaptic vesicles plays a predominant role in enhancing quantal output at this synapse and possibly other central synapses.
