Short-term synaptic plasticity is a defining feature of neuronal activity, but the underlying molecular mechanisms are poorly understood. Depression of synaptic activity might be due to limited vesicle availability, whereas facilitation is thought to result from elevated calcium levels. However, it is unclear whether the strength and direction (facilitation versus depression) of plasticity at a given synapse result from preexisting synaptic strength or whether they are regulated by separate mechanisms. Here we show, in rat hippocampal cell cultures, that increases in the calcium binding protein neuronal calcium sensor-1 (NCS-1) can switch paired-pulse depression to facilitation without altering basal synaptic transmission or initial neurotransmitter release probability. Facilitation persisted during high-frequency trains of stimulation, indicating that NCS-1 can recruit 'dormant' vesicles. Our results suggest that NCS-1 acts as a calcium sensor for short-term plasticity by facilitating neurotransmitter output independent of initial release. We conclude that separate mechanisms are responsible for determining basal synaptic strength and short-term plasticity.
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We thank B. Hargrove for technical assistance and all members of the Schweizer lab. We are also grateful to D. Buonomano, A. Dempsey, J.L. Feldman, M. Klein, N.A. Lambert, K.C. Martin, T.S. Otis, T.J. O'Dell, S.L. Smith and S.A. White for valuable and encouraging discussions, and H.T. Blair for help with statistics. This work was supported by grants from the Whitehall Foundation and the National Institutes of Health (NS41317) to F.E.S.
The authors declare no competing financial interests.
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Sippy, T., Cruz-Martín, A., Jeromin, A. et al. Acute changes in short-term plasticity at synapses with elevated levels of neuronal calcium sensor-1. Nat Neurosci 6, 1031–1038 (2003). https://doi.org/10.1038/nn1117
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