scholarly journals Munc18-1 is a dynamically regulated PKC target during short-term enhancement of transmitter release

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Özgür Genç ◽  
Olexiy Kochubey ◽  
Ruud F Toonen ◽  
Matthijs Verhage ◽  
Ralf Schneggenburger
Keyword(s):  
Transmitter Release ◽  
Molecular Mechanisms ◽  
Gene Replacement ◽  
Target Protein ◽  
Phosphorylation Sites ◽  
Short Term ◽  
Calyx Of Held ◽  
Replacement Strategy ◽  
Kinase C ◽  
Post Tetanic Potentiation

Transmitter release at synapses is regulated by preceding neuronal activity, which can give rise to short-term enhancement of release like post-tetanic potentiation (PTP). Diacylglycerol (DAG) and Protein-kinase C (PKC) signaling in the nerve terminal have been widely implicated in the short-term modulation of transmitter release, but the target protein of PKC phosphorylation during short-term enhancement has remained unknown. Here, we use a gene-replacement strategy at the calyx of Held, a large CNS model synapse that expresses robust PTP, to study the molecular mechanisms of PTP. We find that two PKC phosphorylation sites of Munc18-1 are critically important for PTP, which identifies the presynaptic target protein for the action of PKC during PTP. Pharmacological experiments show that a phosphatase normally limits the duration of PTP, and that PTP is initiated by the action of a ‘conventional’ PKC isoform. Thus, a dynamic PKC phosphorylation/de-phosphorylation cycle of Munc18-1 drives short-term enhancement of transmitter release during PTP.

Distinct Transmitter Release Properties Determine Differences in Short-Term Plasticity at Functional and Silent Synapses

2006 ◽  
Vol 95 (5) ◽  
pp. 3024-3034 ◽  
Author(s):  
Carolina Cabezas ◽  
Washington Buño
Keyword(s):  
Transmitter Release ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Lower Percentage ◽  
Functional Importance ◽  
Short Term ◽  
Short Term Plasticity ◽  
Silent Synapses ◽  
Term Potentiation

Recent evidence suggests that functional and silent synapses are not only postsynaptically different but also presynaptically distinct. The presynaptic differences may be of functional importance in memory formation because a proposed mechanism for long-term potentiation is the conversion of silent synapses into functional ones. However, there is little direct experimentally evidence of these differences. We have investigated the transmitter release properties of functional and silent Schaffer collateral synapses and show that on the average functional synapses displayed a lower percentage of failures and higher excitatory postsynaptic current (EPSC) amplitudes than silent synapses at +60 mV. Moreover, functional but not silent synapses show paired-pulse facilitation (PPF) at +60 mV and thus presynaptic short-term plasticity will be distinct in the two types of synapse. We examined whether intraterminal endoplasmic reticulum Ca2+ stores influenced the release properties of these synapses. Ryanodine (100 μM) and thapsigargin (1 μM) increased the percentage of failures and decreased both the EPSC amplitude and PPF in functional synapses. Caffeine (10 mM) had the opposite effects. In contrast, silent synapses were insensitive to both ryanodine and caffeine. Hence we have identified differences in the release properties of functional and silent synapses, suggesting that synaptic terminals of functional synapses express regulatory molecular mechanisms that are absent in silent synapses.

scholarly journals Short-term plasticity persists in the absence of PKC phosphorylation of Munc18-1

2021 ◽  
Author(s):  
Chih-Chieh Wang ◽  
Christopher Weyrer ◽  
Diasynou Fioravante ◽  
Pascal S. Kaeser ◽  
Wade G. Regehr
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Purkinje Cell ◽  
Granule Cell ◽  
Phorbol Esters ◽  
Short Term ◽  
Short Term Plasticity ◽  
Kinase C ◽  
Hippocampal Ca3 ◽  
Post Tetanic Potentiation

AbstractPost tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knockin mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1 SA mice). Expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3 to CA1 synapse, and the granule cell parallel fiber to Purkinje cell (PF to PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1 SA mice. In Munc18-1 SA mice, 70% of PTP remained at CA3 to CA1 synapses, and the amplitude of PTP was not reduced at PF to PC synapses. These findings indicate that at both CA3 to CA1 and PF to PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1.Significance StatementA leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C phosphorylation of Munc18-1. This study tests this mechanism by creating a knock in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3 to CA1 synapses, or at cerebellar granule cell to Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.

Involvement of protein kinase C in serotonin-induced spike broadening and synaptic facilitation in sensorimotor connections of Aplysia

1992 ◽  
Vol 68 (2) ◽  
pp. 643-651 ◽  
Author(s):  
S. Sugita ◽  
J. R. Goldsmith ◽  
D. A. Baxter ◽  
J. H. Byrne
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Sensory Neurons ◽  
Transmitter Release ◽  
Phorbol Esters ◽  
Kinase Inhibitor ◽  
Model System ◽  
Short Term ◽  
Kinase C ◽  
Kinase A

1. Plasticity at the connections between sensory neurons and their follower cells in Aplysia has been used extensively as a model system to examine mechanisms of simple forms of learning. Earlier studies have concluded that serotonin (5-HT) is a key modulatory transmitter and that it exerts its short-term actions via cAMP-dependent activation of protein kinase A. Subsequently, it has become clear that other kinase systems such as protein kinase C (PKC) also may be involved in the actions of 5-HT. 2. Application of phorbol esters, which activate PKC, produced a slowly developing spike broadening but had little effect on excitability (a process known to be primarily cAMP dependent). Moreover, the effects of phorbol esters and 5-HT on spike duration were not additive, suggesting that they may share some common mechanisms. 3. The protein kinase inhibitor staurosporine suppressed both 5-HT-induced slowly developing spike broadening and, under certain conditions, facilitation of transmitter release. Staurosporine did not inhibit 5-HT-induced enhancement of excitability. The effectiveness of staurosporine on spike broadening was dependent on the time at which spike broadening was examined after application of 5-HT. Staurosporine appeared to have little effect on spike broadening 3 min after application of 5-HT, whereas it inhibited significantly 5-HT-induced spike broadening at later times. The staurosporine-insensitive component of 5-HT-induced spike broadening may be mediated by cAMP. 4. The results suggest that the activation of PKC plays a key role in components of both 5-HT-induced spike broadening and facilitation of synaptic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Contribution of PKC to the maintenance of 5-HT-induced short-term facilitation at sensorimotor synapses of Aplysia

2014 ◽  
Vol 112 (8) ◽  
pp. 1936-1949 ◽  
Author(s):  
Lian Zhou ◽  
Douglas A. Baxter ◽  
John H. Byrne
Keyword(s):  
Protein Kinase ◽  
Transmitter Release ◽  
Model System ◽  
Molecular Processes ◽  
Short Term ◽  
Releasable Pool ◽  
Readily Releasable Pool ◽  
Kinase C ◽  
Sucrose Solutions ◽  
Dependent Processes

Aplysia sensorimotor synapses provide a useful model system for analyzing molecular processes that contribute to heterosynaptic plasticity. For example, previous studies demonstrated that multiple kinase cascades contribute to serotonin (5-HT)-induced short-term synaptic facilitation (STF), including protein kinase A (PKA) and protein kinase C (PKC). Moreover, the contribution of each kinase is believed to depend on the state of the synapse (e.g., depressed or nondepressed) and the time after application of 5-HT. Here, a previously unappreciated role for PKC-dependent processes was revealed to underlie the maintenance of STF at relatively nondepressed synapses. This PKC dependence was revealed when the synapse was stimulated repeatedly after application of 5-HT. The contributions of the PKA and PKC pathways were examined by blocking adenylyl cyclase-coupled 5-HT receptors with methiothepin and by blocking PKC with chelerythrine. STF was assessed 20 s after 5-HT application. The effects of PKC were consistent with enhanced mobilization of transmitter, as assessed by application of hypertonic sucrose solutions to measure the readily releasable pool of vesicles and recovery of the readily releasable pool after depletion. A computational model of transmitter release demonstrated that a PKC-dependent mobilization process was sufficient to explain the maintenance of STF at nondepressed synapses and the facilitation of depressed synapses.

Short-term plasticity at the calyx of held

2002 ◽  
Vol 3 (1) ◽  
pp. 53-64 ◽  
Author(s):  
Henrique von Gersdorff ◽  
J. Gerard G. Borst
Keyword(s):  
Short Term ◽  
Calyx Of Held ◽  
Short Term Plasticity

Synapsin Regulates Basal Synaptic Strength, Synaptic Depression, and Serotonin-Induced Facilitation of Sensorimotor Synapses in Aplysia

2007 ◽  
Vol 98 (6) ◽  
pp. 3568-3580 ◽  
Author(s):  
Diasinou Fioravante ◽  
Rong-Yu Liu ◽  
Anne K. Netek ◽  
Leonard J. Cleary ◽  
John H. Byrne
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Vesicle ◽  
Transmitter Release ◽  
Computational Analysis ◽  
Spontaneous Recovery ◽  
Synaptic Strength ◽  
Short Term ◽  
Homosynaptic Depression ◽  
Heterosynaptic Plasticity

Synapsin is a synaptic vesicle-associated protein implicated in the regulation of vesicle trafficking and transmitter release, but its role in heterosynaptic plasticity remains elusive. Moreover, contradictory results have obscured the contribution of synapsin to homosynaptic plasticity. We previously reported that the neuromodulator serotonin (5-HT) led to the phosphorylation and redistribution of Aplysia synapsin, suggesting that synapsin may be a good candidate for the regulation of vesicle mobilization underlying the short-term synaptic plasticity induced by 5-HT. This study examined the role of synapsin in homosynaptic and heterosynaptic plasticity. Overexpression of synapsin reduced basal transmission and enhanced homosynaptic depression. Although synapsin did not affect spontaneous recovery from depression, it potentiated 5-HT–induced dedepression. Computational analysis showed that the effects of synapsin on plasticity could be adequately simulated by altering the rate of Ca2+-dependent vesicle mobilization, supporting the involvement of synapsin not only in homosynaptic but also in heterosynaptic forms of plasticity by regulating vesicle mobilization.

scholarly journals Altered Short-Term Synaptic Plasticity in Mice Lacking the Metabotropic Glutamate Receptor mGlu7

2002 ◽  
Vol 2 ◽  
pp. 730-737 ◽  
Author(s):  
Trevor J. Bushell ◽  
Gilles Sansig ◽  
Valerie J. Collett ◽  
Herman van der Putten ◽  
Graham L. Collingridge
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Short Term ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Commissural Pathway ◽  
Frequency Facilitation

Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/- mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.

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