Parallel processing of quickly and slowly mobilized reserve vesicles in hippocampal synapses

AbstractQuickly and slowly mobilized reserve vesicles within presynaptic terminals are thought to be contained within separate pools that are connected in series. However, here we use FM-dyes to show that the two types are mobilized in parallel, without intermixing. The result supports a re-conceptualization of synaptic vesicle trafficking, proposed previously, where: (1) active zones contain multiple independent docking/release sites; (2) the release sites vary in probability of catalyzing exocytosis following individual action potentials; and (3), each docked vesicle is connected to a separate reserve. The re-conceptualization is then supported further by evidence that alterations in the timing of reserve pool depletion in synapsin knockouts are largest during lightest use even though alterations in short-term synaptic plasticity are largest during heavy use. The re-conceptualization implies that low release probability sites account for both reluctant readily releasable vesicles and slowly mobilized reserves. Extensive heterogeneity suggests that synapses have the capacity to store information by modulating the ratio of low to high probability release sites.

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Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1524636113 ◽

2016 ◽

Vol 113 (4) ◽

pp. 1062-1067 ◽

Cited By ~ 20

Author(s):

Evanthia Nanou ◽

Jane M. Sullivan ◽

Todd Scheuer ◽

William A. Catterall

Keyword(s):

Synaptic Plasticity ◽

Action Potentials ◽

Hippocampal Neurons ◽

Hippocampal Slices ◽

Short Term ◽

Synaptic Facilitation ◽

Hippocampal Synapses ◽

Presynaptic Nerve Terminals ◽

Sensor Proteins ◽

Kinetics Of

Short-term synaptic plasticity is induced by calcium (Ca2+) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated CaV2.1 Ca2+ channels by Ca2+ sensor proteins induces facilitation of Ca2+ currents and synaptic facilitation in cultured neurons expressing exogenous CaV2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca2+ sensor binding site. This mutation does not alter voltage dependence or kinetics of CaV2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ∼50%. In the presence of EGTA-AM to prevent global increases in free Ca2+, the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca2+ is dependent upon regulation of CaV2.1 channels by Ca2+ sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10–20 Hz. Evidently, regulation of CaV2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.

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