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Quantifying postsynaptic receptor dynamics: insights into synaptic function

Nature Reviews Neuroscience volume 24, pages 4–22 (2023)Cite this article

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Abstract

The molecular composition of presynaptic and postsynaptic neuronal terminals is dynamic, and yet long-term stabilizations in postsynaptic responses are necessary for synaptic development and long-term plasticity. The need to reconcile these concepts is further complicated by learning- and memory-related plastic changes in the molecular make-up of synapses. Advances in single-particle tracking mean that we can now quantify the number and diffusive properties of specific synaptic molecules, while statistical thermodynamics provides a framework to analyse these molecular fluctuations. In this Review, we discuss the use of these approaches to gain quantitative descriptions of the processes underlying the turnover, long-term stability and plasticity of postsynaptic receptors and show how these can help us to understand the balance between local molecular turnover and synaptic structural identity and integrity.

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Fig. 1: Structure and dynamics of postsynaptic receptors at synapses.
Fig. 2: Super-resolved single-particle trajectory analysis.
Fig. 3: Synapse-specific temporal dynamics.
Fig. 4: Biophysical modelling of receptor–scaffold dynamics.

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Acknowledgements

The authors thank V. Hakim for discussions on the biophysics of synapses, and for comments on the manuscript. This work was supported by the French Agence Nationale de la Recherche (Syntrack and Synaptune to A.T.) and the European Research Council (ERC Advanced NVS and ERC Synergy MICROCOPS to A.T.).

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  1. Institut de Biologie de l’École Normale Supérieure, CNRS, Inserm, Université PSL, Paris, France

    Stephanie A. Maynard, Jonas Ranft & Antoine Triller

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  1. Stephanie A. Maynard
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  2. Jonas Ranft
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  3. Antoine Triller
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Contributions

All authors researched data for the article, contributed substantially to discussion of the content, and reviewed and/or edited the manuscript before submission. S.A.M. and J.R. wrote the article.

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Correspondence to Jonas Ranft or Antoine Triller.

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Glossary

Active zone

The site of neurotransmitter release at the presynaptic terminal.

Affinity trapping

The trapping of a molecule in a particular cellular location because of its affinity for its binding partner.

Bayesian inference

A method of statistical inference in which Bayes’s theorem is used to determine the probability that a hypothesis can describe a process (such as the value of a parameter in a model) based on new observations and a given prior probability for the hypothesis (note that a ‘flat’ prior can be used, which assigns equal initial probability to all possible hypotheses).

Blinking

The cycling of fluorophores between light and dark states, enabling the fluorophore to be detected several times.

Brownian motion

The random motion of diffusing particles caused by microscopic collisions with surrounding molecules at finite temperature, first observed by Robert Brown in 1828.

Confined diffusion

Diffusive motion that is confined to a spatial domain of finite size, which manifests itself as a saturation of the mean squared displacement over time.

Continuous-time random walks

A variant of a random walk in which the waiting times between successive steps are drawn from a continuous probability distribution. When the waiting time distribution becomes very broad and heavy tailed, the corresponding continuous-time random walks become subdiffusive.

Deep learning

A class of machine learning that uses multilayer artificial neural networks and that extracts features from a dataset. In imaging, this has been used to reduce imaging time and reconstruct images from undersampled data.

Desensitization

A form of downregulation where an activated receptor decreases its response to an agonist and is hence uncoupled from its signalling cascade.

Diffusion coefficients

The diffusion coefficient is the proportionality constant between the mean squared displacement of a particle and the duration for which the diffusion is observed, as defined for pure diffusion (where the mean squared displacement scales linearly with time).

DNA-PAINT constructs

Oligonucleotides used for single-particle tracking. Reversible hybridization occurs between a docking oligonucleotide strand that is attached to the protein of interest and a fluorophore-conjugated imager strand, enabling single-molecule localization microscopy.

Dwell times

The dwell time is the time for which a receptor stays in the postsynaptic domain after entering from (and before exiting the synapse into) the extrasynaptic space.

Effective potential energies

The effective potential energy is the potential energy that accounts best for the forces inferred (from high-density trajectories) to be acting on the diffusing particles when the forces are proportional to the gradient of the potential energy.

Ergodicity

A property of a dynamical system in which a trajectory visits all of the available phase space such that time averages along trajectories and ensemble averages give the same result.

Fluorescence recovery after photobleaching

A method to determine the kinetics of diffusion of fluorescently labelled molecules by bleaching a small population of the molecules and measuring the time taken for new fluorescent molecules to diffuse into the bleached spot.

Hidden Markov models

(HMMs). Statistical models in which the process being analysed is assumed to be Markovian; that is, its evolution is determined only by the current state of the system but is influenced by an unobserved ‘hidden’ process.

Inference methods

Statistical analyses used to infer the properties of an underlying population that are not directly measurable from a limited number of measurements. This is typically achieved by maximizing the likelihood of the data under the assumption of a given model under certain constraints.

Lateral diffusion

The movement of molecules within the plasma membrane.

Molecular crowding

The situation in which a high concentration of proteins in a localized region of the membrane affects molecule movement in that region by steric hindrance.

Nanobodies

Single-domain antibodies with a molecular mass of 12–15 kDa that are able to selectively bind an antigen.

Phase separation

The generation of two distinct phases from a single homogeneous mixture.

Point spread function

The degree of spreading (blurring) of a point source, such as a fluorophore. Gaussian fitting enables determination of the position of the point source.

Postsynaptic density

(PSD). The electron-dense network of molecules located beneath the postsynaptic membrane of excitatory synapses.

Proteasome

A protein complex that degrades misfolded or damaged proteins.

Quantum dots

Nanometre-sized semiconductors with optoelectronic properties that change as a function of their size. Illuminated by ultraviolet light, they are bright and can be used to track a molecule’s movement for relatively long periods.

Random walk

A conceptualization of diffusive motion in which a ‘walker’ takes sequentially random steps in different directions. For the prototypical random walk, step lengths l are constant and steps occur at constant time steps τ, leading to a diffusion coefficient proportional to l2/τ.

Scaffold proteins

Essential components of the postsynaptic density of excitatory synapses and the postsynaptic domain of inhibitory synapses, involved in binding, clustering and trafficking of postsynaptic receptors.

SPT photoactivated localization microscopy

A fluorescent single-molecule localization microscopy technique using a fluorescent protein attached to a protein of interest.

Subdiffusion

Random, diffusive motion of particles with a sublinear, power-law time dependence of the mean squared displacement. The origins of subdiffusive behaviour can be manifold; for example, subdiffusive behaviour can be caused by transient trapping of particles.

Super-resolution fluorescence microscopy

A series of techniques that enable imaging of fluorescently labelled proteins with resolutions higher than the diffraction limit of light (approximately 200 nm).

Statistical thermodynamics

The description of physical systems that relates the statistics of particles at the microscopic scale (for example, kinetic energies of gas particles) to thermodynamic observables at the macroscopic scale (for example, the pressure of the gas).

Trajectories

The sequences of recorded positions of particles as they move through space.

Ubiquitination

An enzymatic post-translational modification in which a ubiquitin molecule is attached to a substrate protein. This modification regulates the degradation of proteins.

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Maynard, S.A., Ranft, J. & Triller, A. Quantifying postsynaptic receptor dynamics: insights into synaptic function. Nat Rev Neurosci 24, 4–22 (2023). https://doi.org/10.1038/s41583-022-00647-9

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