A new kinetic framework for synaptic vesicle trafficking tested in synapsin knock-outs.

Abstract

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.

DOI: 10.1523/JNEUROSCI.1447-11.2011

10 Figures and Tables

01020201520162017
Citations per Year

Citation Velocity: 5

Averaging 5 citations per year over the last 3 years.

Learn more about how we calculate this metric in our FAQ.

Cite this paper

@article{Gabriel2011ANK, title={A new kinetic framework for synaptic vesicle trafficking tested in synapsin knock-outs.}, author={Thomas Gabriel and Elizabeth Garc{\'i}a-P{\'e}rez and Kashif Mahfooz and Joaqu{\'i}n Go{\~n}i and Rebeca Mart{\'i}nez-Turrillas and Isabel P{\'e}rez-Ota{\~n}o and Donald C. Lo and John F. Wesseling}, journal={The Journal of neuroscience : the official journal of the Society for Neuroscience}, year={2011}, volume={31 32}, pages={11563-77} }