Key Points
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In the CNS, the postsynaptic response to an action potential is variable: neurotransmitter release is probabilistic and the postsynaptic response to neurotransmitter release has variable timing and amplitude.
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Synaptic transmission results from a sequence of reactive and diffusive molecular processes (such as conformational changes, binding events and diffusion) that display stochastic properties at the molecular scale.
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At individual synapses, the number of molecules of a given type is small and the stochastic properties of molecular events cannot be neglected. These stochastic properties underlie the variability of the postsynaptic response evoked by an action potential.
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The stochasticity of presynaptic molecular processes affects the probability of vesicular release, and the stochasticity of postsynaptic molecular processes accounts for the variability in timing and amplitude of the evoked postsynaptic potential.
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The stochasticity of molecular events seems to be in contradiction with the reliability of synaptic transmission, which raises the issues of robustness and sensitivity in the process. Building an integrated view of how the stochasticity of molecular processes contributes to the variability of synaptic transmission but is nevertheless also compatible with a reliable transmission, is a challenge. A key element is that the steps of synaptic transmission are temporally coupled to each other in cascade.
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The characteristics of the coupling between steps are likely to reduce the propagation of fluctuations and/or enhance the sensitivity of the system (the ability to distinguish signal from random fluctuations). These characteristics probably include temporal organization of signalling, spatial organization of molecules, cooperativity and stochastic resonance.
Abstract
The variability of the postsynaptic response following a single action potential arises from two sources: the neurotransmitter release is probabilistic, and the postsynaptic response to neurotransmitter release has variable timing and amplitude. At individual synapses, the number of molecules of a given type that are involved in these processes is small enough that the stochastic (random) properties of molecular events cannot be neglected. How the stochasticity of molecular processes contributes to the variability of synaptic transmission, its sensitivity and its robustness to molecular fluctuations has important implications for our understanding of the mechanistic basis of synaptic transmission and of synaptic plasticity.
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Acknowledgements
The work from Triller's group has been funded by the Institut Nationale de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale de la Recherche (ANR) and the Fondation pour la Recherche Médicale (FRM). We thank B. Barbour and S. Edelstein for critical reading and advice.
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- Stochastic
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A characteristic of a process that is determined by one or more random elements and the proces's statistical properties. Here, stochastic and probabilistic have similar meanings, but we use stochastic for molecular processes and probabilistic for integrated processes.
- Synaptic complex
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A synaptic complex consists of the apposition of a presynaptic active zone with synaptic vesicles and a postsynaptic differentiation characterized by electron-dense material.
- SNARE
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Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein (SNAP) receptor.
- Active zone
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The membrane and submembrane presynaptic region where vesicles are docked and can fuse. This region is about 300nm in diameter.
- Release probability
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At a synapse, an action potential will trigger vesicle exocytosis with a certain probability. This is called release probability and it varies across synapses and can be modulated by dendritic activity.
- Synaptic bouton
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Enlargement of the axon, which frequently contains a single active zone and establishes a synaptic contact with a postsynaptic target .
- Coefficient of variation
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The standard deviation divided by the mean. It gives an estimation of the relative variability of a quantity. A value of 1 is considered large as it means that the standard deviation is equal to 100% of the mean value.
- Deterministic
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The characteristic of a process whose behaviour is described as a function of variables that take unique and non-variable values at each time point in the process. The behaviour of the process is therefore entirely predictable and determined by equations and starting conditions.
- Brownian motion
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A random (stochastic) motion, in which the displacement of a particle during a time t follows a probability distribution. Brownian motion is characterized by a diffusion coefficient. Molecules in fluids (for example, cytoplasm and lipid membrane) undergo Brownian motion.
- Diffusion coefficient
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A parameter characterizing the speed of diffusing molecules. For a brownian mothion in two dimensions, it is the proportionality constant between the explored space and time (for example, measured in μ m2 per s).
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Ribrault, C., Sekimoto, K. & Triller, A. From the stochasticity of molecular processes to the variability of synaptic transmission. Nat Rev Neurosci 12, 375–387 (2011). https://doi.org/10.1038/nrn3025
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DOI: https://doi.org/10.1038/nrn3025
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