Synaptotagmin 7 sculpts short-term plasticity at a high probability synapse

Abstract

Synapses with high release probability (P r ) tend to exhibit short-term synaptic depression. According to the prevailing model, this reflects the temporary depletion of release-ready vesicles after an initial action potential (AP). At the high-P r layer 4 to layer 2/3 (L4-L2/3) synapse in rodent somatosensory cortex, short-term plasticity appears to contradict the depletion model: depression is absent at interstimulus intervals (ISIs) less than 50 ms, and develops to a maximum at ∼200 ms. To understand the mechanism(s) underlying the biphasic time course of short-term plasticity at this synapse, we used whole-cell electrophysiology and two-photon calcium imaging in acute slices from male and female juvenile mice. We tested several candidate mechanisms including neuromodulation, postsynaptic receptor desensitization, and use-dependent changes in presynaptic AP-evoked calcium. We found that, at single L4-L2/3 synapses, P r varies as a function of ISI, giving rise to the distinctive short-term plasticity time course. Furthermore, the higher-than-expected P r at short ISIs depends on expression of synaptotagmin 7 (Syt7). Our results show that two distinct vesicle release processes summate to give rise to short-term plasticity at this synapse: i) a basal, high-P r release mechanism that undergoes rapid depression and recovers slowly (τ = ∼3 s); and ii) a Syt7-dependent mechanism that leads to a transient increase in P r (τ = ∼100 ms) after the initial AP. We thus reveal how these synapses can maintain a very high probability of neurotransmission for multiple APs within a short time frame. Significance Statement Release at single L4-L2/3 synapses violates a commonly held synaptic short-term plasticity rule. Although these synapses transmit with very high probability, they do not undergo profound short-term synaptic depression in the tens of milliseconds following an AP. Syt7 is a calcium-sensing protein important for synaptic facilitation and asynchronous release, but not previously known to play a role at high-P r synapses. We discovered that Syt7-mediated release shapes L4-L2/3 synaptic transmission by effectively counteracting short-term depression for ∼100 ms. We thus establish a molecular basis for a form of information processing at the synaptic level: the combination of these vesicle release properties results in a notch filter, preferentially conveying both very low and very high frequency signals.

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