Synaptic receptor dynamics: From theoretical concepts to deep quantification and chemistry in cellulo

Salvatico, Charlotte; Specht, Christian G.; Triller, Antoine

doi:10.1016/j.neuropharm.2014.09.020

Cited by 22 publications

(33 citation statements)

References 75 publications

(112 reference statements)

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“…Ligand-gated ion channel receptors can move rapidly between extrasynaptic regions and the synaptic stabilization zone (Gerrow and Triller, 2010; Choquet and Triller, 2013; Salvatico et al, 2015). Changes in diffusion dynamics often occur within receptor clusters, and depend on receptor subtype, phosphorylation status and interactions with other proteins (Muir et al, 2010; Muir and Kittler, 2014; Lévi et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

γ1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than γ2-Containing GABA-A Receptors

Dixon

Sah

Keramidas

et al. 2017

Front. Mol. Neurosci.

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GABA-A receptors (GABAARs) are pentameric ligand-gated ion channels that are assembled mainly from α (α1–6), β (β1–3) and γ (γ1–3) subunits. Although GABAARs containing γ2L subunits mediate most of the inhibitory neurotransmission in the brain, significant expression of γ1 subunits is seen in the amygdala, pallidum and substantia nigra. However, the location and function of γ1-containing GABAARs in these regions remains unclear. In “artificial” synapses, where the subunit composition of postsynaptic receptors is specifically controlled, γ1 incorporation slows the synaptic current decay rate without affecting channel deactivation, suggesting that γ1-containing receptors are not clustered and therefore activated by diffuse neurotransmitter. However, we show that γ1-containing receptors are localized at neuronal synapses and form clusters in both synaptic and extrasynaptic regions. In addition, they exhibit rapid membrane diffusion and a higher frequency of exchange between synaptic and perisynaptic populations compared to γ2L-containing GABAARs. A point mutation in the large intracellular domain and a pharmacological analysis reveal that when a single non-conserved γ2L residue is mutated to its γ1 counterpart (T349L), the synaptic current decay is slowed from γ2L- to γ1-like without changing the clustering or diffusion properties of the receptors. In addition, previous fast perfusion and single channel kinetic experiments revealed no difference in the intrinsic closing rates of γ2L- and γ1-containing receptors when expressed in HEK293 cells. These observations together with Monte Carlo simulations of synaptic function confirm that decreased clustering does not control γ1-containing GABAAR kinetics. Rather, they suggest that γ1- and γ2L-containing receptors exhibit differential synaptic current decay rates due to differential gating dynamics when localized at the synapse.

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Section: Resultsmentioning

confidence: 99%

γ1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than γ2-Containing GABA-A Receptors

Dixon

Sah

Keramidas

et al. 2017

Front. Mol. Neurosci.

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“…Synaptic membrane domains are crowded with molecules [3,15], which is expected [4,6,16,17,43] to affect diffusion and reaction processes at synaptic domains. To account for molecular crowding in our model, we impose [36,37,62] the constraint that the rates of all reaction and diffusion processes that increase the receptor or scaffold number at a lattice site i are ∝ (1 − N r i − N s i ), where N r i /ǫ r and N s i /ǫ s are the occupation numbers of receptors and scaffolds at site i with the normalization constants ǫ r and ǫ s so that, at each site, the number of receptors and scaffolds cannot increase beyond 1/ǫ r and 1/ǫ s , respectively.…”

Section: Reaction-diffusion Model Of Synaptic Receptor-scaffold Dmentioning

confidence: 99%

“…The stability and plasticity of synapses are thought to play central roles in memory formation and learning [1,2]. In particular, neurotransmitter receptor molecules, concentrated in postsynaptic membrane domains along with scaffolds and other kinds of proteins [3,4], are crucial for signal transmission across chemical synapses [2,[5][6][7]. The strength of the transmitted signal depends on the number of receptors localized in synaptic domains [2,6], and regulation of the receptor number in synaptic domains provides one mechanism for postsynaptic plasticity [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…The strength of the transmitted signal depends on the number of receptors localized in synaptic domains [2,6], and regulation of the receptor number in synaptic domains provides one mechanism for postsynaptic plasticity [8][9][10]. With the advent of in vivo superresolution light microscopy [11][12][13][14], the multiscale properties of synaptic domains-from the stochastic diffusion trajectories of individual synaptic receptors to the overall size and stability of synaptic domains-can now be studied quantitatively [3,4,10,15]. A central discovery [3,4,10,15] here is that synaptic receptors [12,16,17], as well as their associated scaffolds [3,[18][19][20], turn over rapidly, with individual molecules entering and leaving synaptic domains on typical time scales as short as seconds.…”

Section: Introductionmentioning

confidence: 99%

“…With the advent of in vivo superresolution light microscopy [11][12][13][14], the multiscale properties of synaptic domains-from the stochastic diffusion trajectories of individual synaptic receptors to the overall size and stability of synaptic domains-can now be studied quantitatively [3,4,10,15]. A central discovery [3,4,10,15] here is that synaptic receptors [12,16,17], as well as their associated scaffolds [3,[18][19][20], turn over rapidly, with individual molecules entering and leaving synaptic domains on typical time scales as short as seconds. In contrast, synaptic domains of a well-defined characteristic size can persist over months or even longer periods of time [21,22], which may [2-4, 6, 8-10, 15] constitute part of the cellular basis for memory formation and learning.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stochastic lattice model of synaptic membrane protein domains

Kahraman

Haselwandter

2017

Phys. Rev. E

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Neurotransmitter receptor molecules, concentrated in synaptic membrane domains along with scaffolds and other kinds of proteins, are crucial for signal transmission across chemical synapses. In common with other membrane protein domains, synaptic domains are characterized by low protein copy numbers and protein crowding, with rapid stochastic turnover of individual molecules. We study here in detail a stochastic lattice model of the receptor-scaffold reaction-diffusion dynamics at synaptic domains that was found previously to capture, at the mean-field level, the self-assembly, stability, and characteristic size of synaptic domains observed in experiments. We show that our stochastic lattice model yields quantitative agreement with mean-field models of nonlinear diffusion in crowded membranes. Through a combination of analytic and numerical solutions of the master equation governing the reaction dynamics at synaptic domains, together with kinetic Monte Carlo simulations, we find substantial discrepancies between mean-field and stochastic models for the reaction dynamics at synaptic domains. Based on the reaction and diffusion properties of synaptic receptors and scaffolds suggested by previous experiments and mean-field calculations, we show that the stochastic reaction-diffusion dynamics of synaptic receptors and scaffolds provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the observed single-molecule trajectories, and spatial heterogeneity in the effective rates at which receptors and scaffolds are recycled at the cell membrane. Our work sheds light on the physical mechanisms and principles linking the collective properties of membrane protein domains to the stochastic dynamics that rule their molecular components.

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Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: A pilot study

et al. 2018

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Live attenuated vaccines have proved to be mostly valuable in the prevention of infectious diseases in humans, especially in developing countries. The safety and potency of vaccine, and the consistency of vaccine batch-to-batch manufacturing, must be proven before being administrated to humans. For now, the tests used to control vaccine safety largely involve animal testing. For live viral vaccines, regulations require suppliers to demonstrate the absence of neurovirulence in animals, principally in non-human primates and mice. In a search to reduce the use of animals and embracing the 3Rs principles (Replacement, Reduction, Refinement in the use of laboratory animals), we developed a new Blood-Brain Barrier Minibrain (BBB-Minibrain) in cellulo device to evaluate the neuroinvasiveness/neurovirulence of live Yellow Fever virus (YFV) vaccines. A pilot study was performed using the features of two distinct YFV strains, with the ultimate goal of proposing a companion test to characterize YFV neurovirulence. Here, we demonstrate that the BBB-Minibrain model is a promising alternative to consider for future replacement of YFV vaccine in vivo neurovirulence testing (see graphical abstract).

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Synaptic receptor dynamics: From theoretical concepts to deep quantification and chemistry in cellulo

Cited by 22 publications

References 75 publications

γ1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than γ2-Containing GABA-A Receptors

γ1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than γ2-Containing GABA-A Receptors

Stochastic lattice model of synaptic membrane protein domains

Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: A pilot study

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