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Posttetanic potentiation critically depends on an enhanced Ca(2+) sensitivity of vesicle fusion mediated by presynaptic PKC.

ABSTRACT: Activity-dependent enhancement of transmitter release is a common form of presynaptic plasticity, but the underlying signaling mechanisms have remained largely unknown, perhaps because of the inaccessibility of most CNS nerve terminals. Here we investigated the signaling steps that underlie posttetanic potentiation (PTP), a form of presynaptic plasticity found at many CNS synapses. Direct whole-cell recordings from the large calyx of Held nerve terminals with the perforated patch-clamp technique showed that PTP was not mediated by changes in the presynaptic action potential waveform. Ca(2+) imaging revealed a slight increase of the presynaptic Ca(2+) transient during PTP ( approximately 15%), which, however, was too small to explain a large part of PTP. The presynaptic PKC pathway was critically involved in PTP because (i) PTP was occluded by activation of PKC with phorbol esters, and (ii) PTP was largely (by approximately two-thirds) blocked by the PKC inhibitors, Ro31-8220 or bisindolylmaleimide. Activation of PKC during PTP most likely acts directly on the presynaptic release machinery, because in presynaptic Ca(2+) uncaging experiments, activation of PKC by phorbol ester greatly increased the Ca(2+) sensitivity of vesicle fusion in a Ro31-8220-sensitive manner ( approximately 300% with small Ca(2+) uncaging stimuli), but only slightly increased presynaptic voltage-gated Ca(2+) currents ( approximately 15%). We conclude that a PKC-dependent increase in the Ca(2+) sensitivity of vesicle fusion is a key step in the enhancement of transmitter release during PTP.

SUBMITTER: Korogod N

PROVIDER: S-EPMC2000442 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Posttetanic potentiation critically depends on an enhanced Ca(2+) sensitivity of vesicle fusion mediated by presynaptic PKC.

Korogod Natalya N Lou Xuelin X Schneggenburger Ralf R

Proceedings of the National Academy of Sciences of the United States of America 20070920 40

Activity-dependent enhancement of transmitter release is a common form of presynaptic plasticity, but the underlying signaling mechanisms have remained largely unknown, perhaps because of the inaccessibility of most CNS nerve terminals. Here we investigated the signaling steps that underlie posttetanic potentiation (PTP), a form of presynaptic plasticity found at many CNS synapses. Direct whole-cell recordings from the large calyx of Held nerve terminals with the perforated patch-clamp technique ...[more]

PMID: 17884983

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Project description:Understanding how neuromodulators regulate behavior requires investigating their effects on functional neural systems, but also their underlying cellular mechanisms. Utilizing extensively characterized lamprey motor circuits, and the unique access to reticulospinal presynaptic terminals in the intact spinal cord that initiate these behaviors, we investigated effects of presynaptic G-protein-coupled receptors on locomotion from the systems level, to the molecular control of vesicle fusion. 5-HT inhibits neurotransmitter release via a Gbetagamma interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that promotes kiss-and-run vesicle fusion. In the lamprey spinal cord, we demonstrate that, although presynaptic 5-HT receptors inhibit evoked neurotransmitter release from reticulospinal command neurons, their activation does not abolish locomotion but rather modulates locomotor rhythms. Liberation of presynaptic Gbetagamma causes substantial inhibition of AMPA receptor-mediated synaptic responses but leaves NMDA receptor-mediated components of neurotransmission mostly intact. Because Gbetagamma binding to the SNARE complex is displaced by Ca(2+)-synaptotagmin binding, 5-HT-mediated inhibition displays Ca(2+) sensitivity. We show that, as Ca(2+) accumulates presynaptically during physiological bouts of activity, 5-HT/Gbetagamma-mediated presynaptic inhibition is relieved, leading to a frequency-dependent increase in synaptic concentrations of glutamate. This frequency-dependent phenomenon mirrors a shift in the vesicle fusion mode and a recovery of AMPA receptor-mediated EPSCs from inhibition without a modification of NMDA receptor EPSCs. We conclude that activation of presynaptic 5-HT G-protein-coupled receptors state-dependently alters vesicle fusion properties to shift the weight of NMDA versus AMPA receptor-mediated responses at excitatory synapses. We have therefore identified a novel mechanism in which modification of vesicle fusion modes may profoundly alter locomotor behavior.

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Posttetanic potentiation critically depends on an enhanced Ca(2+) sensitivity of vesicle fusion mediated by presynaptic PKC.

Publications

Posttetanic potentiation critically depends on an enhanced Ca(2+) sensitivity of vesicle fusion mediated by presynaptic PKC.

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