Delayed Release of Neurotransmitter from Cerebellar Granule Cells

Atluri, Pradeep P.; Regehr, Wade G.

doi:10.1523/jneurosci.18-20-08214.1998

Cited by 219 publications

(273 citation statements)

References 47 publications

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“…These developing neurons in autaptic culture (4 -10 d in vitro) undergo robust asynchronous release without the requirement to use Sr 2ϩ or other agents to prolong time course of release (Abdul-Ghani et al, 1996). Previous studies as well as our own work indicate that asynchronous release is dependent on elevated intraterminal residual Ca 2ϩ concentration because it is selectively blocked by treatment with the relatively slow chelator EGTA-AM (Cummings et al, 1996;Atluri and Regehr, 1998;Otsu et al, 2004). Given that the individual AMPAR mEPSCs making up the tail have relatively rapid decay kinetics (Ͻ5 msec), the decay of the tail current reflects the time course of asynchronous release frequency.…”

Section: A Switch To Asynchronous Release During Trains Of Stimulationmentioning

confidence: 82%

Optical Postsynaptic Measurement of Vesicle Release Rates for Hippocampal Synapses Undergoing Asynchronous Release during Train Stimulation

Otsu

Murphy²

2004

J. Neurosci.

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Developing hippocampal neurons in microisland culture were found to undergo rapid depression of excitatory synaptic activity caused by consumption of their readily releasable pool (RRP) of vesicles in response to 20 Hz trains of stimulation. Associated with depression was a switch to an asynchronous release mode that maintained transmission at a high steady-state rate equivalent to ϳ2.1 RRPs per second. We have applied postsynaptic Ca 2ϩ imaging to directly monitor these asynchronous release events to estimate both the steady rate of transmitter release and the number of quanta within the RRP at individual hippocampal synapses. Based on the frequency of asynchronous release measured at individual synapses postsynaptically using Ca 2ϩ imaging (5-17 sec after train stimulation) and with knowledge of the time course by which asynchronous release rates decay, we estimate that individual hippocampal synapses exhibit (in response to train stimulation) peak release rates of up to 21 quanta per second from an RRP that contains, on average, 10 quanta. Use-dependent block of evoked synaptic activity by MK-801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate] confirmed that synapses undergoing asynchronous release are not significantly different from the general population with regard to their composition of NMDA receptor and/or release probability. Given that high-frequency trains deplete the synapse of readily releasable quanta (and that these release rates can only be maintained for a few seconds), these high rates of asynchronous release likely reflect refilling of vesicles from a reserve pool and not necessarily the continuous action of a relatively slow clathrin-and endosomedependent process.

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Section: A Switch To Asynchronous Release During Trains Of Stimulationmentioning

confidence: 82%

Optical Postsynaptic Measurement of Vesicle Release Rates for Hippocampal Synapses Undergoing Asynchronous Release during Train Stimulation

Otsu

Murphy²

2004

J. Neurosci.

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“…Ca 2+ entry through Ca V 2 channels triggers the fusion of synaptic vesicles, initiating synaptic transmission that occurs in two phases: a fast synchronous component and a slower asynchronous component that builds during trains of action potentials. The fraction of synaptic vesicle exocytosis that is mediated by the slower asynchronous release process varies from synapse to synapse (38)(39)(40)(41)(42)(43)(44). In some synapses, asynchronous neurotransmitter release can exceed …”

Section: Resultsmentioning

confidence: 99%

Asynchronous Ca ² ⁺ current conducted by voltage-gated Ca ²⁺ (Ca _V )-2.1 and Ca _V 2.2 channels and its implications for asynchronous neurotransmitter release

Few¹,

Nanou²,

Watari

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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We have identified an asynchronously activated Ca 2+ current through voltage-gated Ca 2+ (Ca V )-2.1 and Ca V 2.2 channels, which conduct P/Qand N-type Ca 2+ currents that initiate neurotransmitter release. In nonneuronal cells expressing Ca V 2.1 or Ca V 2.2 channels and in hippocampal neurons, prolonged Ca 2+ entry activates a Ca 2+ current, I Async , which is observed on repolarization and decays slowly with a halftime of 150-300 ms. I Async is not observed after L-type Ca 2+ currents of similar size conducted by Ca V 1.2 channels. I Async is Ca 2+ -selective, and it is unaffected by changes in Na + , K + , Cl − , or H + or by inhibitors of a broad range of ion channels. During trains of repetitive depolarizations, I Async increases in a pulse-wise manner, providing Ca 2+ entry that persists between depolarizations. In single-cultured hippocampal neurons, trains of depolarizations evoke excitatory postsynaptic currents that show facilitation followed by depression accompanied by asynchronous postsynaptic currents that increase steadily during the train in parallel with I Async . I Async is much larger for slowly inactivating Ca V 2.1 channels containing β 2a -subunits than for rapidly inactivating channels containing β 1b -subunits. I Async requires global rises in intracellular Ca 2+ , because it is blocked when Ca 2+ is chelated by 10 mM EGTA in the patch pipette. Neither mutations that prevent Ca 2+ binding to calmodulin nor mutations that prevent calmodulin regulation of Ca V 2.1 block I Async . The rise of I Async during trains of stimuli, its decay after repolarization, its dependence on global increases of Ca 2+ , and its enhancement by β 2a -subunits all resemble asynchronous release, suggesting that I Async is a Ca 2+ source for asynchronous neurotransmission.asynchronous synaptic transmission | exocytosis V oltage-gated Ca 2+ (Ca V ) channels are activated by depolarization and conduct inward Ca 2+ currents that initiate many cellular responses to electrical signaling (1). Ca V 2 channels conduct P/Q-, N-, and R-type currents in presynaptic nerve terminals, and Ca 2+ entry through these channels initiates neurotransmitter release at conventional synapses (1-3). P/Q-and N-type Ca 2+ currents conducted by Ca V 2.1 and Ca V 2.2 channels, respectively, are more efficiently coupled to neurotransmitter release than Rtype Ca 2+ currents conducted by Ca V 2.3 channels (4, 5). Neurotransmitter release occurs in two phases: a fast synchronous (phasic) component and a slow asynchronous (tonic) component (6). The slower asynchronous component of release is proposed to result from residual Ca 2+ remaining after an action potential acting on a different Ca 2+ sensor than the sensor for synchronous neurotransmitter release (6-8). Remarkably, when synchronous release is prevented by deletion of its Ca 2+ sensor synaptotagmin, the asynchronous release process can cause exocytosis of the entire readily releasable pool, suggesting a functional competition between synchronous and asynchronous release processes for the ...

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“…Asynchronous release termed here is vesicle release that takes place after synchronous release decays fully and before the next stimulation. It is therefore different from delayed release, which was elicited for a prolonged period after (high-frequency) stimulation (in the order of hundreds of milliseconds to seconds) (Midlei and Thies, 1971;Rahamimoff and Yaari, 1973;Zengel and Magleby, 1981;Zucker and Lara-Estralla, 1983;Atluri and Regehr, 1998). It is possible that the slowly releasing vesicles contribute to synchronous release, although the contribution must be relatively small.…”

Section: Discussionmentioning

confidence: 98%

Roles of the Fast-Releasing and the Slowly Releasing Vesicles in Synaptic Transmission at the Calyx of Held

Sakaba¹

2006

J. Neurosci.

121

150

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In the calyx of Held, fast and slow components of neurotransmitter release can be distinguished during a step depolarization. The two components show different sensitivity to molecular/pharmacological manipulations. Here, their roles during a high-frequency train of action potential (AP)-like stimuli were examined by using both deconvolution of EPSCs and presynaptic capacitance measurements. During a 100 Hz train of AP-like stimuli, synchronous release showed a pronounced depression within the 20 stimuli. Asynchronous release persisted during the train, was variable in its amount, and was more prominent during a 300 Hz train. We have shown previously that slowly releasing vesicles were recruited faster than fast-releasing vesicles after depletion. By further slowing recovery of the fastreleasing vesicles by inhibiting calmodulin-dependent processes (Sakaba and Neher, 2001b), the slowly releasing vesicles were isolated during recovery from vesicle depletion. When a high-frequency train was applied, the isolated slowly releasing vesicles were released predominantly asynchronously. In contrast, synchronous release was mediated mainly by the fast-releasing vesicles. The results suggest that fast-releasing vesicles contribute mainly to synchronous release and that depletion of fast-releasing vesicles shape the synaptic depression of the synchronous phase of EPSCs, whereas slowly releasing vesicles are released mainly asynchronously during highfrequency stimulation. The latter is less subject to depression presumably because of a rapid vesicular recruitment process, which is a characteristic of this component.

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Delayed Release of Neurotransmitter from Cerebellar Granule Cells

Cited by 219 publications

References 47 publications

Optical Postsynaptic Measurement of Vesicle Release Rates for Hippocampal Synapses Undergoing Asynchronous Release during Train Stimulation

Optical Postsynaptic Measurement of Vesicle Release Rates for Hippocampal Synapses Undergoing Asynchronous Release during Train Stimulation

Asynchronous Ca ² ⁺ current conducted by voltage-gated Ca ²⁺ (Ca _V )-2.1 and Ca _V 2.2 channels and its implications for asynchronous neurotransmitter release

Roles of the Fast-Releasing and the Slowly Releasing Vesicles in Synaptic Transmission at the Calyx of Held

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Delayed Release of Neurotransmitter from Cerebellar Granule Cells

Cited by 219 publications

References 47 publications

Optical Postsynaptic Measurement of Vesicle Release Rates for Hippocampal Synapses Undergoing Asynchronous Release during Train Stimulation

Optical Postsynaptic Measurement of Vesicle Release Rates for Hippocampal Synapses Undergoing Asynchronous Release during Train Stimulation

Asynchronous Ca 2 + current conducted by voltage-gated Ca 2+ (Ca V )-2.1 and Ca V 2.2 channels and its implications for asynchronous neurotransmitter release

Roles of the Fast-Releasing and the Slowly Releasing Vesicles in Synaptic Transmission at the Calyx of Held

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Asynchronous Ca ² ⁺ current conducted by voltage-gated Ca ²⁺ (Ca _V )-2.1 and Ca _V 2.2 channels and its implications for asynchronous neurotransmitter release