Synapsin II and calcium regulate vesicle docking and the cross‐talk between vesicle pools at the mouse motor terminals

Coleman, William L.; Bill, Cynthia A.; Simsek-Duran, Fatma; Lónárt, György; Samigullin, Dmitry; Bykhovskaia, Maria

doi:10.1113/jphysiol.2008.154666

Cited by 31 publications

(33 citation statements)

References 75 publications

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“…Synapsin II, which is a stronger effector of transmitter release at our preparation than synapsin I, was shown to inhibit quantal release at low Ca 2+ conditions (Samigullin et al, 2004; Coleman et al, 2008), while Rab3a was shown to promote it (Coleman et al, 2007, 2009b). The above studies also revealed that synapsin II maintains the pool of intraterminal vesicles, while Rab3a maintains the pool of docked vesicles.…”

Section: Introductionmentioning

confidence: 79%

“…The DKO breeders obtained this way were used to start the colony, and the experiments were performed on the first generation of their progeny. The control colony (WT) started from the strain B6;129F2/J (Jackson Laboratory), a genetic match to the KO, was the same as in all of our previous studies (Samigullin et al, 2004; Coleman et al, 2008, Coleman and Bykhovskaia, 2009a,b). All the animals were kept at standard conditions at room temperature and on a 12h dark/light cycle.…”

Section: Methodsmentioning

confidence: 99%

“…The regulation of release time-course by synapsin I (Hilfiker et al, 1998; Coleman and Bykhovskaia, 2009a) suggests its function in the latest stages of exocytosis. In contrast, synapsin II appears to have a specific role in preventing synaptic depression and maintaining the reserve pool of vesicles (Rosahl et al, 1995; Coleman et al, 2008; Gitler et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

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Cooperative regulation of neurotransmitter release by Rab3a and synapsin II

Coleman

Bykhovskaia

2010

Molecular and Cellular Neuroscience

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To understand how the presynaptic proteins synapsin and Rab3a may interact in the regulation of the synaptic vesicle cycle and the release process, we derived a double knockout (DKO) mouse lacking both synapsin II and Rab3a. We found that Rab3a deletion rescued epileptic-like seizures typical for synapsin II gene deleted animals (SynII(−)). Furthermore, action potential evoked release was drastically reduced in DKO synapses, although spontaneous release remained normal. At low Ca2+ conditions, quantal content was equally reduced in Rab3a(−) and DKO synapses, but as Ca2+ concentration increased, the increase in quantal content was more prominent in Rab3a(−). Electron microscopy analysis revealed that DKO synapses have a combined phenotype, with docked vesicles being reduced similar to Rab3a(−), and intraterminal vesicles being depleted similar to SynII(−). Consistently, both SynII(−) and DKO terminals had increased synaptic depression and incomplete recovery. Taken together, our results suggest that synapsin II and Rab3a have separate roles in maintaining the total store of synaptic vesicles and cooperate in promoting the latest steps of neuronal secretion.

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Section: Introductionmentioning

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cooperative regulation of neurotransmitter release by Rab3a and synapsin II

Coleman

Bykhovskaia

2010

Molecular and Cellular Neuroscience

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“…Synapsins are a family of neuron-specific phosphoproteins that bind synaptic vesicles to the cytoskeleton (Bloom et al 2003;Coleman et al 2008;Fdez and Hilfiker 2006;Ferreira and Rapoport 2002;Villanueva et al 2006). Three mammalian synapsin genes have been identified to date, which through alternative splicing give rise to two isoforms each, producing synapsins Ia, Ib, IIa, and IIb Sudhof et al 1989).…”

Section: Introductionmentioning

confidence: 99%

Role of AP-2α Transcription Factor in the Regulation of Synapsin II Gene Expression by Dopamine D1 and D2 Receptors

Skoblenick

Argintaru

et al. 2009

J Mol Neurosci

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Synapsins are a family of neuron-specific phosphoproteins involved in synaptic vesicle docking, synaptogenesis, and synaptic plasticity. Previous studies have reported an increase in synapsin II protein by dopaminergic agents in the striatum, medial prefrontal cortex, and nucleus accumbens. This study investigated the mechanistic pathway involved in synapsin II regulation by dopaminergic drugs using primary midbrain neurons to determine which of several transcription factors regulates synapsin II expression. Protein kinase A (PKA) participation in the signaling pathway was examined using selective PKA inhibitors, which reduced synapsin II expression in cell cultures while dopaminergic agents were unable to increase synapsin II in the presence of the PKA inhibitor. Transcription factor involvement was further investigated using separate cultures treated with antisense deoxyoligonucleotides (ADONs) against the following transcription factors: activating protein 2 alpha (AP-2alpha), early growth response factor 1 (EGR-1), or polyoma enhancer activator-3 (PEA-3). Selective knockdown of AP-2alpha by ADONs reduced synapsin II levels, whereas treatment with EGR-1 and PEA-3 ADONs did not affect synapsin II expression. Furthermore, dopaminergic agents were no longer able to influence synapsin II concentrations following AP-2alpha knockdown. Collectively, these results indicate that a cyclic adenosine-3',5'-monophosphate/PKA-dependent mechanism involving the AP-2alpha transcription factor is likely responsible for the increase in neuronal synapsin II following dopamine D1 receptor stimulation or dopamine D2 receptor inhibition.

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“…Or, vesicle trafficking might follow more complicated rules at other synapse types (Richards et al, 2003;Crowley et al, 2007;Coleman et al, 2008;Sakaba, 2008). Nevertheless, Schaffer collateral synapses are similar to the majority of excitatory synapses throughout the brain, both at the level of electron microscopy (Peters and Palay, 1996) and in that they are typically driven sparingly during ordinary use (Ranck, 1973), but when driven extensively they exhibit substantial short-term depression (Chance et al, 1998).…”

Section: Comparison To Other Synapse Typesmentioning

confidence: 99%

A New Kinetic Framework for Synaptic Vesicle Trafficking Tested in Synapsin Knock-Outs

Gabriel¹,

García‐Pérez²,

Mahfooz³

et al. 2011

J. Neurosci.

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At least two rate-limiting mechanisms in vesicle trafficking operate at mouse Schaffer collateral synapses, but their molecular/physical identities are unknown. The first mechanism determines the baseline rate at which reserve vesicles are supplied to a readily releasable pool. The second causes the supply rate to depress threefold when synaptic transmission is driven hard for extended periods. Previous models invoked depletion of a reserve vesicle pool to explain the reductions in the supply rate, but the mass-action assumption at their core is not compatible with kinetic measurements of neurotransmission under maximal-use conditions. Here we develop a new theoretical model of rate-limiting steps in vesicle trafficking that is compatible with previous and new measurements. A physical interpretation is proposed where local reserve pools consisting of four vesicles are tethered to individual release sites and are replenished stochastically in an all-or-none fashion. We then show that the supply rate depresses more rapidly in synapsin knock-outs and that the phenotype can be fully explained by changing the value of the single parameter in the model that would specify the size of the local reserve pools. Vesicle-trafficking rates between pools were not affected. Finally, optical imaging experiments argue against alternative interpretations of the theoretical model where vesicle trafficking is inhibited without reserve pool depletion. This new conceptual framework will be useful for distinguishing which of the multiple molecular and cell biological mechanisms involved in vesicle trafficking are rate limiting at different levels of synaptic throughput and are thus candidates for physiological and pharmacological modulation.

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Synapsin II and calcium regulate vesicle docking and the cross‐talk between vesicle pools at the mouse motor terminals

Abstract: The synapsins, an abundant and highly conserved family of proteins that associate with synaptic vesicles, have been implicated in regulating the synaptic vesicle cycle. However, it has not been determined whether synapsin directly regulates the number of docked vesicles.

Cited by 31 publications

References 75 publications

Cooperative regulation of neurotransmitter release by Rab3a and synapsin II

Cooperative regulation of neurotransmitter release by Rab3a and synapsin II

Role of AP-2α Transcription Factor in the Regulation of Synapsin II Gene Expression by Dopamine D1 and D2 Receptors

A New Kinetic Framework for Synaptic Vesicle Trafficking Tested in Synapsin Knock-Outs

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