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1. Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Author: Teja Wolfgang Groemer, Antoine Triller, Hanns Ulrich Zeilhofer, Kristina Becker, Volker Eulenburg, and Cord Michael Becker
Subjects: glycine receptor, pain, glycinergic inhibition, nociception, synaptic clustering, spastic, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Glycine receptors (GlyRs) are the primary mediators of fast inhibitory transmission in the mammalian spinal cord, where they modulate sensory and motor signaling. Mutations in GlyR genes as well as some other genes underlie the hereditary disorder hyperekplexia, characterized by episodic muscle stiffness and exaggerated startle responses. Here, we have investigated pain-related behavior and GlyR expression in the spinal cord of the GlyR deficient mutant mouse spastic (spa). In spastic mice, the GlyR number is reduced due to a β subunit gene (Glrb) mutation resulting in aberrant splicing of GlyRβ transcripts. Via direct physical interaction with the GlyR anchoring protein gephyrin, this subunit is crucially involved in the postsynaptic clustering of heteromeric GlyRs. We show that the mutation differentially affects aspects of the pain-related behavior of homozygous Glrbspa/Glrbspa mice. While response latencies to noxious heat were unchanged, chemically induced pain-related behavior revealed a reduction of the licking time and an increase in flinching in spastic homozygotes during both phases of the formalin test. Mechanically induced nocifensive behavior was reduced in spastic mice, although hind paw inflammation (by zymosan) resulted in allodynia comparable to wild-type mice. Immunohistochemical staining of the spinal cord revealed a massive reduction of dotted GlyRα subunit immunoreactivity in both ventral and dorsal horns, suggesting a reduction of clustered receptors at synaptic sites. Transcripts for all GlyRα subunit variants, however, were not reduced throughout the dorsal horn of spastic mice. These findings suggest that the loss of functional GlyRβ subunits and hence synaptically localized GlyRs compromises sensory processing differentially, depending on stimulus modality.
Published: 2022
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2. cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABAAR Trapping at Inhibitory Synapses

Author: Fumihiro Niwa, Angela Patrizio, Antoine Triller, and Christian G. Specht
Subjects: Science
Abstract: Summary: GABAA and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different receptors can be regulated independently from one another. Here we show that cAMP-dependent signaling reduces gephyrin phosphorylation at residue S270 in spinal cord neurons. Although no ultrastructural changes of the synaptic scaffold were detected using super-resolution imaging, gephyrin de-phosphorylation was associated with a selective increase in GABAAR diffusion and the loss of the receptors from synapses. As opposed to the PKA-dependent dispersal of α3-containing GlyRs, the regulation of gephyrin phosphorylation and GABAAR dynamics acts via non-canonical EPAC signaling. Subtype-specific changes in receptor mobility can thus differentially contribute to changes in inhibitory synaptic strength, such as the disinhibition of spinal cord neurons during inflammatory processes. : Molecular Neuroscience; Cellular Neuroscience; Sensory Neuroscience Subject Areas: Molecular Neuroscience, Cellular Neuroscience, Sensory Neuroscience
Published: 2019
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3. Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses

Author: Stephanie A Maynard, Philippe Rostaing, Natascha Schaefer, Olivier Gemin, Adrien Candat, Andréa Dumoulin, Carmen Villmann, Antoine Triller, and Christian G Specht
Subjects: single molecule localization microscopy, correlative light and electron microscopy, electron microscopy, hyperekplexia, oscillator mouse model, glycine receptor, Medicine, Science, Biology (General), QH301-705.5
Abstract: Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far, the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy. We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains, and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.
Published: 2021
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4. Unique properties of dually innervated dendritic spines in pyramidal neurons of the somatosensory cortex uncovered by 3D correlative light and electron microscopy.

Author: Olivier Gemin, Pablo Serna, Joseph Zamith, Nora Assendorp, Matteo Fossati, Philippe Rostaing, Antoine Triller, and Cécile Charrier
Subjects: Biology (General), QH301-705.5
Abstract: Pyramidal neurons (PNs) are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization, but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light-electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 PNs of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually innervated and 38% of inhibitory synapses localized to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.
Published: 2021
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5. Sushi domain-containing protein 4 controls synaptic plasticity and motor learning

Author: Inés González-Calvo, Keerthana Iyer, Mélanie Carquin, Anouar Khayachi, Fernando A Giuliani, Séverine M Sigoillot, Jean Vincent, Martial Séveno, Maxime Veleanu, Sylvana Tahraoui, Mélanie Albert, Oana Vigy, Célia Bosso-Lefèvre, Yann Nadjar, Andréa Dumoulin, Antoine Triller, Jean-Louis Bessereau, Laure Rondi-Reig, Philippe Isope, and Fekrije Selimi
Subjects: synapse, plasticity, cerebellum, proteostasis, Medicine, Science, Biology (General), QH301-705.5
Abstract: Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here, we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.
Published: 2021
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6. Inhibitory Receptor Diffusion Dynamics

Author: Stephanie A. Maynard and Antoine Triller
Subjects: diffusion-trapping, inhibitory synapse, GABAA receptor, glycine receptor, gephyrin, single-particle tracking, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: The dynamic modulation of receptor diffusion-trapping at inhibitory synapses is crucial to synaptic transmission, stability, and plasticity. In this review article, we will outline the progression of understanding of receptor diffusion dynamics at the plasma membrane. We will discuss how regulation of reversible trapping of receptor-scaffold interactions in combination with theoretical modeling approaches can be used to quantify these chemical interactions at the postsynapse of living cells.
Published: 2019
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7. Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation

Author: Saad Hannan, Kim Gerrow, Antoine Triller, and Trevor G. Smart
Subjects: AMPK, bungarotoxin binding site, Ca2+ signaling, excitotoxicity, GABA receptors, GABAB receptors, glutamate receptors, hippocampus, homeostatic signaling, lateral diffusion, NMDA receptors, phosphorylation, presynaptic terminal, quantum dots, receptor mobility, single-particle tracking, sushi domains, Biology (General), QH301-705.5
Abstract: Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs) using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca2+-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity.
Published: 2016
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8. Data in support of the identification of neuronal and astrocyte proteins interacting with extracellularly applied oligomeric and fibrillar α-synuclein assemblies by mass spectrometry

Author: Amulya Nidhi Shrivastava, Virginie Redeker, Nicolas Fritz, Laura Pieri, Leandro G. Almeida, Maria Spolidoro, Thomas Liebmann, Luc Bousset, Marianne Renner, Clément Léna, Anita Aperia, Ronald Melki, and Antoine Triller
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Science (General), Q1-390
Abstract: α-Synuclein (α-syn) is the principal component of Lewy bodies, the pathophysiological hallmark of individuals affected by Parkinson disease (PD). This neuropathologic form of α-syn contributes to PD progression and propagation of α-syn assemblies between neurons. The data we present here support the proteomic analysis used to identify neuronal proteins that specifically interact with extracellularly applied oligomeric or fibrillar α-syn assemblies (conditions 1 and 2, respectively) (doi: 10.15252/embj.201591397 [1]). α-syn assemblies and their cellular partner proteins were pulled down from neuronal cell lysed shortly after exposure to exogenous α-syn assemblies and the associated proteins were identified by mass spectrometry using a shotgun proteomic-based approach. We also performed experiments on pure cultures of astrocytes to identify astrocyte-specific proteins interacting with oligomeric or fibrillar α-syn (conditions 3 and 4, respectively). For each condition, proteins interacting selectively with α-syn assemblies were identified by comparison to proteins pulled-down from untreated cells used as controls. The mass spectrometry data, the database search and the peak lists have been deposited to the ProteomeXchange Consortium database via the PRIDE partner repository with the dataset identifiers PRIDE: http://www.ebi.ac.uk/pride/archive/projects/PXD002256 to PRIDE: http://www.ebi.ac.uk/pride/archive/projects/PXD002263 and doi: 10.6019/http://www.ebi.ac.uk/pride/archive/projects/PXD002256 to 10.6019/http://www.ebi.ac.uk/pride/archive/projects/PXD002263. Keywords: Parkinson׳s disease, Alpha-synuclein assemblies, Proteomic Analysis, Pull down
Published: 2016
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9. Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium

Author: Hiroko Bannai, Fumihiro Niwa, Mark W. Sherwood, Amulya Nidhi Shrivastava, Misa Arizono, Akitoshi Miyamoto, Kotomi Sugiura, Sabine Lévi, Antoine Triller, and Katsuhiko Mikoshiba
Subjects: Biology (General), QH301-705.5
Abstract: GABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses.
Published: 2015
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10. Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity.

Author: Despoina Goniotaki, Asvin K K Lakkaraju, Amulya N Shrivastava, Pamela Bakirci, Silvia Sorce, Assunta Senatore, Rajlakshmi Marpakwar, Simone Hornemann, Fabrizio Gasparini, Antoine Triller, and Adriano Aguzzi
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrPC), we investigated the impact of mGluR1 and mGluR5 inhibition on prion toxicity ex vivo and in vivo. We found that pharmacological inhibition of mGluR1 and mGluR5 antagonized dose-dependently the neurotoxicity triggered by prion infection and by prion-mimetic anti-PrPC antibodies in organotypic brain slices. Prion-mimetic antibodies increased mGluR5 clustering around dendritic spines, mimicking the toxicity of Aβ oligomers. Oral treatment with the mGluR5 inhibitor, MPEP, delayed the onset of motor deficits and moderately prolonged survival of prion-infected mice. Although group-I mGluR inhibition was not curative, these results suggest that it may alleviate the neurological dysfunctions induced by prion diseases.
Published: 2017
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11. An aggregation-removal model for the formation and size determination of post-synaptic scaffold domains.

Author: Jonas Ranft, Leandro G Almeida, Pamela C Rodriguez, Antoine Triller, and Vincent Hakim
Subjects: Biology (General), QH301-705.5
Abstract: The formation and stability of synapses are key questions in neuroscience. Post-synaptic domains have been classically conceived as resulting from local insertion and turnover of proteins at the synapse. However, insertion is likely to occur outside the post-synaptic domains and advances in single-molecule imaging have shown that proteins diffuse in the plane of the membrane prior to their accumulation at synapses. We quantitatively investigated this scenario using computer simulations and mathematical analysis, taking for definiteness the specific case of inhibitory synapse components, i.e., the glycine receptor (GlyR) and the associated gephyrin scaffolding protein. The observed domain sizes of scaffold clusters can be explained by a dynamic balance between the aggregation of gephyrin proteins diffusing while bound to GlyR and their turnover at the neuron membrane. We also predict the existence of extrasynaptic clusters with a characteristic size distribution that significantly contribute to the size fluctuations of synaptic domains. New super-resolution data for gephyrin proteins established the existence of extrasynaptic clusters the sizes of which are consistent with the model predictions in a range of model parameters. At a general level, our results highlight aggregation with removal as a non-equilibrium phase separation which produces structures of tunable size.
Published: 2017
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12. The Role of Synaptopodin in Membrane Protein Diffusion in the Dendritic Spine Neck.

Author: Lili Wang, Andréa Dumoulin, Marianne Renner, Antoine Triller, and Christian G Specht
Subjects: Medicine, Science
Abstract: The dynamic exchange of neurotransmitter receptors at synapses relies on their lateral diffusion in the plasma membrane. At synapses located on dendritic spines this process is limited by the geometry of the spine neck that restricts the passage of membrane proteins. Biochemical compartmentalisation of the spine is believed to underlie the input-specificity of excitatory synapses and to set the scale on which functional changes can occur. Synaptopodin is located predominantly in the neck of dendritic spines, and is thus ideally placed to regulate the exchange of synaptic membrane proteins. The central aim of our study was to assess whether the presence of synaptopodin influences the mobility of membrane proteins in the spine neck and to characterise whether this was due to direct molecular interactions or to spatial constraints that are related to the structural organisation of the neck. Using single particle tracking we have identified a specific effect of synaptopodin on the diffusion of metabotropic mGluR5 receptors in the spine neck. However, super-resolution STORM/PALM imaging showed that this was not due to direct interactions between the two proteins, but that the presence of synaptopodin is associated with an altered local organisation of the F-actin cytoskeleton, that in turn could restrict the diffusion of membrane proteins with large intracellular domains through the spine neck. This study contributes new data on the way in which the spine neck compartmentalises excitatory synapses. Our data complement models that consider the impact of the spine neck as a function of its shape, by showing that the internal organisation of the neck imposes additional physical barriers to membrane protein diffusion.
Published: 2016
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13. Correction: Gephyrin-Independent GABAR Mobility and Clustering during Plasticity.

Author: Fumihiro Niwa, Hiroko Bannai, Misa Arizono, Kazumi Fukatsu, Antoine Triller, and Katsuhiko Mikoshiba
Subjects: Medicine, Science
Published: 2012
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14. Diffusion barriers constrain receptors at synapses.

Author: Marianne Renner, Claude Schweizer, Hiroko Bannai, Antoine Triller, and Sabine Lévi
Subjects: Medicine, Science
Abstract: The flux of neurotransmitter receptors in and out of synapses depends on receptor interaction with scaffolding molecules. However, the crowd of transmembrane proteins and the rich cytoskeletal environment may constitute obstacles to the diffusion of receptors within the synapse. To address this question, we studied the membrane diffusion of the γ-aminobutyric acid type A receptor (GABA(A)R) subunits clustered (γ2) or not (α5) at inhibitory synapses in rat hippocampal dissociated neurons. Relative to the extrasynaptic region, γ2 and α5 showed reduced diffusion and increased confinement at both inhibitory and excitatory synapses but they dwelled for a short time at excitatory synapses. In contrast, γ2 was ~3-fold more confined and dwelled ~3-fold longer in inhibitory synapses than α5, indicating faster synaptic escape of α5. Furthermore, using a gephyrin dominant-negative approach, we showed that the increased residency time of γ2 at inhibitory synapses was due to receptor-scaffold interactions. As shown for GABA(A)R, the excitatory glutamate receptor 2 subunit (GluA2) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) had lower mobility in both excitatory and inhibitory synapses but a higher residency time at excitatory synapses. Therefore barriers impose significant diffusion constraints onto receptors at synapses where they accumulate or not. Our data further reveal that the confinement and the dwell time but not the diffusion coefficient report on the synapse specific sorting, trapping and accumulation of receptors.
Published: 2012
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15. Gephyrin-independent GABA(A)R mobility and clustering during plasticity.

Author: Fumihiro Niwa, Hiroko Bannai, Misa Arizono, Kazumi Fukatsu, Antoine Triller, and Katsuhiko Mikoshiba
Subjects: Medicine, Science
Abstract: The activity-dependent modulation of GABA-A receptor (GABA(A)R) clustering at synapses controls inhibitory synaptic transmission. Several lines of evidence suggest that gephyrin, an inhibitory synaptic scaffold protein, is a critical factor in the regulation of GABA(A)R clustering during inhibitory synaptic plasticity induced by neuronal excitation. In this study, we tested this hypothesis by studying relative gephyrin dynamics and GABA(A)R declustering during excitatory activity. Surprisingly, we found that gephyrin dispersal is not essential for GABA(A)R declustering during excitatory activity. In cultured hippocampal neurons, quantitative immunocytochemistry showed that the dispersal of synaptic GABA(A)Rs accompanied with neuronal excitation evoked by 4-aminopyridine (4AP) or N-methyl-D-aspartic acid (NMDA) precedes that of gephyrin. Single-particle tracking of quantum dot labeled-GABA(A)Rs revealed that excitation-induced enhancement of GABA(A)R lateral mobility also occurred before the shrinkage of gephyrin clusters. Physical inhibition of GABA(A)R lateral diffusion on the cell surface and inhibition of a Ca(2+) dependent phosphatase, calcineurin, completely eliminated the 4AP-induced decrease in gephyrin cluster size, but not the NMDA-induced decrease in cluster size, suggesting the existence of two different mechanisms of gephyrin declustering during activity-dependent plasticity, a GABA(A)R-dependent regulatory mechanism and a GABA(A)R-independent one. Our results also indicate that GABA(A)R mobility and clustering after sustained excitatory activity is independent of gephyrin.
Published: 2012
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16. Super-resolution dynamic imaging of dendritic spines using a low-affinity photoconvertible actin probe.

Author: Ignacio Izeddin, Christian G Specht, Mickaël Lelek, Xavier Darzacq, Antoine Triller, Christophe Zimmer, and Maxime Dahan
Subjects: Medicine, Science
Abstract: The actin cytoskeleton of dendritic spines plays a key role in morphological aspects of synaptic plasticity. The detailed analysis of the spine structure and dynamics in live neurons, however, has been hampered by the diffraction-limited resolution of conventional fluorescence microscopy. The advent of nanoscopic imaging techniques thus holds great promise for the study of these processes. We implemented a strategy for the visualization of morphological changes of dendritic spines over tens of minutes at a lateral resolution of 25 to 65 nm. We have generated a low-affinity photoconvertible probe, capable of reversibly binding to actin and thus allowing long-term photoactivated localization microscopy of the spine cytoskeleton. Using this approach, we resolve structural parameters of spines and record their long-term dynamics at a temporal resolution below one minute. Furthermore, we have determined changes in the spine morphology in response to pharmacologically induced synaptic activity and quantified the actin redistribution underlying these changes. By combining PALM imaging with quantum dot tracking, we could also simultaneously visualize the cytoskeleton and the spine membrane, allowing us to record complementary information on the morphological changes of the spines at super-resolution.
Published: 2011
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17. Lateral diffusion on tubular membranes: quantification of measurements bias.

Author: Marianne Renner, Yegor Domanov, Fanny Sandrin, Ignacio Izeddin, Patricia Bassereau, and Antoine Triller
Subjects: Medicine, Science
Abstract: Single Particle Tracking (SPT) is a powerful technique for the analysis of the lateral diffusion of the lipid and protein components of biological membranes. In neurons, SPT allows the study of the real-time dynamics of receptors for neurotransmitters that diffuse continuously in and out synapses. In the simplest case where the membrane is flat and is parallel to the focal plane of the microscope the analysis of diffusion from SPT data is relatively straightforward. However, in most biological samples the membranes are curved, which complicates analysis and may lead to erroneous conclusions as for the mode of lateral diffusion. Here we considered the case of lateral diffusion in tubular membranes, such as axons, dendrites or the neck of dendritic spines. Monte Carlo simulations allowed us to evaluate the error in diffusion coefficient (D) calculation if the curvature is not taken into account. The underestimation is determined by the diameter of the tubular surface, the frequency of image acquisition and the degree of mobility itself. We found that projected trajectories give estimates that are 25 to 50% lower than the real D in case of 2D-SPT over the tubular surface. The use of 3D-SPT improved the measurements if the frequency of image acquisition was fast enough in relation to the mobility of the molecules and the diameter of the tube. Nevertheless, the calculation of D from the components of displacements in the axis of the tubular structure gave accurate estimate of D, free of geometrical artefacts. We show the application of this approach to analyze the diffusion of a lipid on model tubular membranes and of a membrane-bound GFP on neurites from cultured rat hippocampal neurons.
Published: 2011
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18. The neuronal splicing factor Nova co-localizes with target RNAs in the dendrite

Author: Claudia Racca, Alejandra Gardiol, Taesun Eom, Jernej Ule, Antoine Triller, and Robert B Darnell
Subjects: RNA Splicing, GIRK2, HITS-CLIP, inhibitory glycine receptor, nova, RNA localization, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Nova proteins are neuron-specific RNA binding proteins targeted by autoantibodies in a disorder manifest by failure of motor inhibition, and they regulate splicing and alternative 3’ processing. Nova regulates splicing of RNAs encoding synaptic proteins, including the inhibitory glycine receptor α2 subunit (GlyRα2), and binds to others, including the GIRK2 channel. We found that Nova harbors functional NES and NLS elements, shuttles between the nucleus and cytoplasm, and that 50% of the protein localizes to the soma-dendritic compartment. Immunofluoresence and EM analysis of spinal cord motor neurons demonstrated that Nova co-localizes beneath synaptic contacts in dendrites with the same RNA, GlyRα2, whose splicing it regulates in the nucleus. HITS-CLIP identified intronic and 3’ UTR sites where Nova binds to GlyRα2 and GIRK2 transcripts in the brain. This led directly to the identification of a 3’ UTR localization element that mediates Nova-dependent localization of GIRK2 in primary neurons. These data demonstrate that HITS-CLIP can identify functional RNA localization elements, and they suggest new links between the regulation of nuclear RNA processing and mRNA localization.
Published: 2010
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19. Cellular transport and membrane dynamics of the glycine receptor

Author: Andrea Dumoulin, Antoine Triller, and Matthias Kneussel
Subjects: Cytoskeleton, Diffusion, gephyrin, Neuronal activity, transport, glycine receptor, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Regulation of synaptic transmission is essential to tune individual-to-network neuronal activity. One way to modulate synaptic strength is to regulate neurotransmitter receptor numbers at postsynaptic sites. This can be achieved either through plasma membrane insertion of receptors derived from intracellular vesicle pools, a process depending on active cytoskeleton transport, or through surface membrane removal via endocytosis. In parallel, lateral diffusion events along the plasma membrane allow the exchange of receptor molecules between synaptic and extrasynaptic compartments, contributing to synaptic strength regulation. In recent years, results obtained from several groups studying glycine receptor (GlyR) trafficking and dynamics shed light on the regulation of synaptic GlyR density. Here, we review i) proteins and mechanisms involved in GlyR cytoskeletal transport, ii) the diffusion dynamics of GlyR and of its scaffolding protein gephyrin that control receptor numbers, and its relationship with synaptic plasticity, and iii) adaptative changes in GlyR diffusion in response to global activity modifications, as a homeostatic mechanism.
Published: 2010
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20. Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function.

Author: Anne Roumier, Olivier Pascual, Catherine Béchade, Shirley Wakselman, Jean-Christophe Poncer, Eleonore Réal, Antoine Triller, and Alain Bessis
Subjects: Medicine, Science
Abstract: BackgroundEpidemiological studies have linked maternal infection during pregnancy to later development of neuropsychiatric disorders in the offspring. In mice, experimental inflammation during embryonic development impairs behavioral and cognitive performances in adulthood. Synaptic dysfunctions may be at the origin of cognitive impairments, however the link between prenatal inflammation and synaptic defects remains to be established.Methodology/principal findingsIn this study, we show that prenatal alteration of microglial function, including inflammation, induces delayed synaptic dysfunction in the adult. DAP12 is a microglial signaling protein expressed around birth, mutations of which in the human induces the Nasu-Hakola disease, characterized by early dementia. We presently report that synaptic excitatory currents in mice bearing a loss-of-function mutation in the DAP12 gene (DAP12(KI) mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12(KI) P0 pups cultured without microglia develop similar synaptic alterations, suggesting that a prenatal dysfunction of microglia may impact synaptic function in the adult. As we observed that DAP12(KI) microglia overexpress genes for IL1beta, IL6 and NOS2, which are inflammatory proteins, we analyzed the impact of a pharmacologically-induced prenatal inflammation on synaptic function. Maternal injection of lipopolysaccharides induced activation of microglia at birth and alteration of glutamatergic synapses in the adult offspring. Finally, neurons cultured from neonates born to inflamed mothers and cultured without microglia also displayed altered neuronal activity.Conclusion/significanceOur results demonstrate that prenatal inflammation is sufficient to induce synaptic alterations with delay. We propose that these alterations triggered by prenatal activation of microglia provide a cellular basis for the neuropsychiatric defects induced by prenatal inflammation.
Published: 2008
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21. Quantifying postsynaptic receptor dynamics: insights into synaptic function

Author: Stephanie A. Maynard, Jonas Ranft, and Antoine Triller
Subjects: General Neuroscience
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.
Published: 2022
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22. AUTS2 gene dosage affects synaptic AMPA receptors via a local dendritic spine AUTS2-TTC3-AKT-mTORC1 signaling dysfunction

Author: Aude-Marie Lepagnol-Bestel, Arnaud Duchon, Julia Viard, Mirna Kvajo, Rachel Daudin, Malik Khelfaoui, Simon Haziza, Yann Loe-Mie, Mattia Aime, Futoshi Suizu, Marie-Christine Birling, Mounia Bensaid, Sylvie Jacquot, Pascale Koebel, Céline Reverdy, Jean-Christophe Rain, Masayuki Noguchi, Xavier Marquez, Antoine Triller, Yann Humeau, Yann Hérault, Maria Karayiorgou, Joseph A. Gogos, and Michel Simonneau
Abstract: The Human 1.2-MbAUTS2locus on chromosome 7q11.22 encodes a 1259-aa full-length protein, and a 711-aa C-terminal isoform. Functions of these AUTS2 proteins are only partly known. The major traits found in patients displayingAUTS2locus mutations are Intellectual Disabilities, microcephaly attention deficit hyperactivity disorder (ADHD) (54%), and autistic traits. Furthermore,AUTS2common variants were recently found associated to alcohol consumption and dyslexia using GWAS approaches. Auts2 localizes mainly in cell nuclei. We evidenced by super-resolution that Auts2 is present in dendritic spines. Auts2 interacts with Ttc3, the Akt2 E3 ligase, and negatively regulates Akt2 ubiquitination. Auts2 haploinsufficiency affects Akt/mTorc1 pathway with a decrease in AMPA and NMDA receptor subunits and in synaptic currents. Akt2 injection in postsynaptic neurons is sufficient to reverse changes in synaptic currents generated by Auts2 haploinsufficiency. Using chromosome engineering based on targeted meiotic recombination, we generated two mouse models withAuts2locus deletion and duplication. DeletedAuts2locus mice display stereotypies (rearing), perseveration and abnormal recognition memory. DuplicatedAuts2locus mice display similar perseveration and abnormal recognition memory but also a decrease in cued and contextual fear memory. Gene dosage induce changes in brain sub-region neuronal networks. In the thalamo-lateral amygdala pathway linked to cued fear memory, we found synaptic impairments linked to AMPA receptors, with a specific decrease in pAKT/total AKT ratio in duplicated Auts2 mice. Altogether, our study thereby provides a novel mechanistic and potentially therapeutic understanding of synaptic AKT/mTORC1 deregulated signaling and its related behavioral and cognitive phenotypes.
Published: 2022
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23. Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep

Author: Maria J Pinto, Léa Cottin, Florent Dingli, Victor Laigle, Luís F. Ribeiro, Antoine Triller, Fiona J Henderson, Damarys Loew, Véronique Fabre, Alain Bessis, and Bessis, Alain
Subjects: [SDV] Life Sciences [q-bio]
Abstract: The time we spend asleep is adjusted to previous time spent awake, and therefore believed to be under tight homeostatic control. Here, we establish microglia as a new cellular component of the sleep homeostat circuit. By using quantitative phosphoproteomics we demonstrate that microglia-derived TNFα controls thousands of phosphorylation sites during the sleep period. Substrates of microglial TNFα comprise sleep-promoting kinases and numerous synaptic proteins, including a subset whose phosphorylation status codes sleep need and determines sleep duration. As a result, lack of microglial TNFα attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation.
Published: 2022
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24. Increased Confinement and Polydispersity of STIM1 and Orai1 after Ca2+ Store Depletion

Author: Changbong Hyeon, Adolfo Alsina, Ben Zhong Tang, Xianan Qin, Hajin Kim, Chan Young Park, Sang Kwon Lee, Chao Wu, Chenglong Yu, Hojeong Park, Antoine Triller, Teng Liu, Lei Liu, Jun Chu, and Hyokeun Park
Subjects: inorganic chemicals, 0303 health sciences, Chemistry, Anomalous diffusion, ORAI1, Endoplasmic reticulum, Diffusion, Calcium channel, Biophysics, STIM1, 03 medical and health sciences, 0302 clinical medicine, Membrane, Radius of gyration, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: STIM1 (a Ca2+ sensor in the endoplasmic reticulum (ER) membrane) and Orai1 (a pore-forming subunit of the Ca2+-release-activated calcium channel in the plasma membrane) diffuse in the ER membrane and plasma membrane, respectively. Upon depletion of Ca2+ stores in the ER, STIM1 translocates to the ER-plasma membrane junction and binds Orai1 to trigger store-operated Ca2+ entry. However, the motion of STIM1 and Orai1 during this process and its roles to Ca2+ entry is poorly understood. Here, we report real-time tracking of single STIM1 and Orai1 particles in the ER membrane and plasma membrane in living cells before and after Ca2+ store depletion. We found that the motion of single STIM1 and Orai1 particles exhibits anomalous diffusion both before and after store depletion, and their mobility-measured by the radius of gyration of the trajectories, mean-square displacement, and generalized diffusion coefficient-decreases drastically after store depletion. We also found that the measured displacement distribution is non-Gaussian, and the non-Gaussian parameter drastically increases after store depletion. Detailed analyses and simulations revealed that single STIM1 and Orai1 particles are confined in the compartmentalized membrane both before and after store depletion, and the changes in the motion after store depletion are explained by increased confinement and polydispersity of STIM1-Orai1 complexes formed at the ER-plasma membrane junctions. Further simulations showed that this increase in the confinement and polydispersity after store depletion localizes a rapid increase of Ca2+ influx, which can facilitate the rapid activation of local Ca2+ signaling pathways and the efficient replenishing of Ca2+ store in the ER in store-operated Ca2+ entry.
Published: 2020
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25. Microglial TNFα controls synaptic GABAARs, slow waves and memory consolidation during sleep

Author: Maria Joana Pinto, Lucy Bizien, Julie M.J. Fabre, Nina Ðukanović, Léa Cottin, Valentin Lepetz, Fiona Henderson, Marine Pujol, Romain W. Sala, Thibault Tarpin, Daniela Popa, Antoine Triller, Clément Léna, Véronique Fabre, and Alain Bessis
Subjects: nervous system
Abstract: Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces microglia-dependent synaptic enrichment of GABAARs in a manner dependent on microglial TNFα and P2RX7. We further show that microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunts sleep-dependent memory consolidation. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of synaptic GABAARs, sculpt sleep slow waves and support sleep-dependent memory consolidation.
Published: 2022
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26. cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABAAR Trapping at Inhibitory Synapses

Author: Angela Patrizio, Fumihiro Niwa, Christian G. Specht, Antoine Triller, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, animal structures, [SDV]Life Sciences [q-bio], 02 engineering and technology, Molecular neuroscience, Inhibitory postsynaptic potential, Article, 03 medical and health sciences, Cellular neuroscience, lcsh:Science, Receptor, Glycine receptor, Multidisciplinary, Gephyrin, biology, GABAA receptor, Chemistry, musculoskeletal, neural, and ocular physiology, fungi, 021001 nanoscience & nanotechnology, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, nervous system, Cellular Neuroscience, biology.protein, Phosphorylation, lcsh:Q, Molecular Neuroscience, Sensory Neuroscience, 0210 nano-technology
Abstract: Summary GABAA and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different receptors can be regulated independently from one another. Here we show that cAMP-dependent signaling reduces gephyrin phosphorylation at residue S270 in spinal cord neurons. Although no ultrastructural changes of the synaptic scaffold were detected using super-resolution imaging, gephyrin de-phosphorylation was associated with a selective increase in GABAAR diffusion and the loss of the receptors from synapses. As opposed to the PKA-dependent dispersal of α3-containing GlyRs, the regulation of gephyrin phosphorylation and GABAAR dynamics acts via non-canonical EPAC signaling. Subtype-specific changes in receptor mobility can thus differentially contribute to changes in inhibitory synaptic strength, such as the disinhibition of spinal cord neurons during inflammatory processes., Graphical Abstract, Highlights • Differential signaling downstream of cAMP regulates mixed inhibitory synapses • EPAC reduces gephyrin S270 phosphorylation but not the copy numbers at synapses • Gephyrin de-phosphorylation reduces GABAAR binding and increases receptor diffusion • PKA phosphorylation of GlyRα3L at residue S346 mobilizes synaptic receptors, Molecular Neuroscience; Cellular Neuroscience; Sensory Neuroscience
Published: 2019
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27. Author Reply to Peer Reviews of Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses

Author: Christian G Specht, Antoine Triller, Carmen Villmann, Andréa Dumoulin, Adrien Candat, Olivier Gemin, Natascha Schaefer, Philippe Rostaing, and Stephanie A Maynard
Published: 2021
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28. NMDARs in granule cells contribute to parallel fiber–Purkinje cell synaptic plasticity and motor learning

Author: Caroline Mailhes-Hamon, Antoine Triller, Guy Bouvier, Martijn Schonewille, Annick Ayon, Chris I. De Zeeuw, Alexandra B. Nelson, Philippe Rostaing, Allison E. Girasole, Mariano Casado, and Neurosciences
Subjects: Cerebellum, Multidisciplinary, cerebellum, Chemistry, Purkinje cell, Parallel fiber, Biological Sciences, pre-NMDARs, Synapse, medicine.anatomical_structure, nervous system, Purkinje cells, nitric oxide, Postsynaptic potential, Synaptic plasticity, medicine, NMDA receptor, Motor learning, motor learning, Neuroscience
Abstract: Significance Learning depends on synaptic plasticity. The signaling mechanisms that control induction of plasticity determine the learning rules at the specific synapse involved. Moreover, the relationship between the activity patterns of synaptic inputs and the type, direction, and level of plasticity induced may evolve during development. Here, we establish a key link between receptor activation presynaptic to cerebellar Purkinje cells, downstream signaling mechanisms, and the ability of adult animals to learn a cerebellar motor task., Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic N-methyl-D-aspartate receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers NO signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-PC (PF-PC) synapses. Consistent with this finding, the selective deletion of GC NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.
Published: 2021
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29. Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses

Author: Philippe Rostaing, Andréa Dumoulin, Olivier Gemin, Antoine Triller, Carmen Villmann, Christian G. Specht, Stephanie A Maynard, Natascha Schaefer, and Adrien Candat
Subjects: Mouse, QH301-705.5, Science, Neurotransmission, Biology, Inhibitory postsynaptic potential, Synapse, Mice, Receptors, Glycine, Postsynaptic potential, medicine, Animals, correlative light and electron microscopy, Hyperekplexia, Biology (General), Glycine receptor, oscillator mouse model, electron microscopy, Molecular Structure, spinal cord, Spinal cord, medicine.anatomical_structure, hyperekplexia, Synapses, Medicine, Brainstem, single molecule localization microscopy, glycine receptor, medicine.symptom, Neuroscience, Research Article
Abstract: Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy (SR-CLEM). We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs μm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.
Published: 2021
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30. Differential regulation of glycinergic and GABAergic nanocolumns at mixed inhibitory synapses

Author: Pascal Legendre, Christian G. Specht, Hervé Le Corronc, Xiaojuan Yang, Antoine Triller, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), East China Normal University [Shangaï] (ECNU), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Maladies et hormones du système nerveux (DHNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, Hal Sorbonne Université, and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: Scaffold protein, [SDV]Life Sciences [q-bio], Biochemistry, Article, sub-synaptic domains, 03 medical and health sciences, 0302 clinical medicine, Genetics, Receptor, Molecular Biology, Glycine receptor, 030304 developmental biology, Neurons, 0303 health sciences, GABAAR, Gephyrin, biology, Chemistry, GABAA receptor, GABA A R, Articles, Receptors, GABA-A, single‐molecule localization microscopy, [SDV] Life Sciences [q-bio], sub‐synaptic domains, Spinal Cord, direct stochastic optical reconstruction microscopy, GlyR, Synapses, biology.protein, GABAergic, Phosphorylation, Signal transduction, Carrier Proteins, Neuroscience, single-molecule localization microscopy, 030217 neurology & neurosurgery
Abstract: Super‐resolution imaging has revealed that key synaptic proteins are dynamically organized within sub‐synaptic domains (SSDs). To examine how different inhibitory receptors are regulated, we carried out dual‐color direct stochastic optical reconstruction microscopy (dSTORM) of GlyRs and GABAARs at mixed inhibitory synapses in spinal cord neurons. We show that endogenous GlyRs and GABAARs as well as their common scaffold protein gephyrin form SSDs that align with pre‐synaptic RIM1/2, thus creating trans‐synaptic nanocolumns. Strikingly, GlyRs and GABAARs occupy different sub‐synaptic spaces, exhibiting only a partial overlap at mixed inhibitory synapses. When network activity is increased by 4‐aminopyridine treatment, the GABAAR copy numbers and the number of GABAAR SSDs are reduced, while GlyRs remain largely unchanged. This differential regulation is likely the result of changes in gephyrin phosphorylation that preferentially occurs outside of SSDs. The activity‐dependent regulation of GABAARs versus GlyRs suggests that different signaling pathways control the receptors' sub‐synaptic clustering. Taken together, our data reinforce the notion that the precise sub‐synaptic organization of GlyRs, GABAARs, and gephyrin has functional consequences for the plasticity of mixed inhibitory synapses., This study analyzes the internal organization of mixed inhibitory spinal cord synapses using dSTORM and reveals the existence of trans‐synaptic nanocolumns containing GlyRs and GABAARs that are differentially regulated in response to altered network activity.
Published: 2021
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31. Sushi domain-containing protein 4 controls synaptic plasticity and motor learning

Author: Keerthana Iyer, Fernando A Giuliani, Laure Rondi-Reig, Philippe Isope, Yann Nadjar, Antoine Triller, Jean-Louis Bessereau, Mélanie Albert, Andréa Dumoulin, Séverine M. Sigoillot, Oana Vigy, Maxime Veleanu, Jean Vincent, Mélanie Carquin, Anouar Khayachi, Célia Bosso-Lefèvre, Martial Séveno, Fekrije Selimi, Inés González-Calvo, Sylvana Tahraoui, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CeZaMe - Cervelet, navigation et mémoire = Memory, Navigation and Aging (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, Hal Sorbonne Université, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Sushi domain, cerebellum, QH301-705.5, Science, [SDV]Life Sciences [q-bio], Protein subunit, AMPA receptor, Motor Activity, General Biochemistry, Genetics and Molecular Biology, neuroscience, Synapse, Mice, 03 medical and health sciences, 0302 clinical medicine, Ubiquitin, synapse, Animals, Learning, Biology (General), mouse, Complement Inactivator Proteins, Neuronal Plasticity, proteostasis, General Immunology and Microbiology, biology, General Neuroscience, Membrane Proteins, General Medicine, Transmembrane protein, [SDV] Life Sciences [q-bio], 030104 developmental biology, Proteostasis, plasticity, Synaptic plasticity, biology.protein, Medicine, Neuroscience, 030217 neurology & neurosurgery, Research Article
Abstract: Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here, we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.
Published: 2021
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32. Reciprocal stabilization of glycine receptors and gephyrin scaffold proteins at inhibitory synapses

Author: Christian G. Specht, Vincent Hakim, Thomas Chapdelaine, Jonas Ranft, Antoine Triller, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique et Neuroscience Théoriques, Laboratoire de physique de l'ENS - ENS Paris (LPENS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Sorbonne Université (SU)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Sorbonne Université (SU)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Maladies et hormones du système nerveux (DHNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-12-BSV4-0019,Synaptune,Nouveaux mecanismes de régulation de la localization des récepteurs inhibiteurs(2012), ANR-17-CE13-0030,SynTrack,Libération des neurotransmetteurs et des récepteurs pendant la transmission synaptique: visualisation en temps réèl(2017), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physique de l'ENS - ENS Paris (LPENS (UMR_8023)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Département de Physique de l'ENS-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Département de Physique de l'ENS-PSL, Ranft, Jonas, BLANC - Nouveaux mecanismes de régulation de la localization des récepteurs inhibiteurs - - Synaptune2012 - ANR-12-BSV4-0019 - BLANC - VALID, Libération des neurotransmetteurs et des récepteurs pendant la transmission synaptique: visualisation en temps réèl - - SynTrack2017 - ANR-17-CE13-0030 - AAPG2017 - VALID, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Scaffold protein, immunoimmobilisation (IMMO), [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biophysics, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Neurotransmission, mEos4b, Reciprocal GlyR-gephyrin stabilisation glycine receptor (GlyR), 03 medical and health sciences, Receptors, Glycine, 0302 clinical medicine, Dendra2, Neurotransmitter receptor, Postsynaptic potential, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], crosslinking, Receptor, Glycine receptor, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [PHYS]Physics [physics], 0303 health sciences, fluorescence recovery after photobleaching (FRAP), [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Gephyrin, biology, Chemistry, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Membrane Proteins, Fluorescence recovery after photobleaching, Articles, Receptors, GABA-A, photochromism, gephyrin, fluorescence decay after photoconversion (FDAP), Synapses, biology.protein, 030217 neurology & neurosurgery
Abstract: Postsynaptic scaffold proteins immobilize neurotransmitter receptors in the synaptic membrane opposite to presynaptic vesicle release sites, thus ensuring efficient synaptic transmission. At inhibitory synapses in the spinal cord, the main scaffold protein gephyrin assembles in dense molecule clusters that provide binding sites for glycine receptors (GlyRs). Gephyrin and GlyRs can also interact outside of synapses, where they form receptor-scaffold complexes. Although several models for the formation of postsynaptic scaffold domains in the presence of receptor-scaffold interactions have been advanced, a clear picture of the coupled dynamics of receptors and scaffold proteins at synapses is lacking. To characterize the GlyR and gephyrin dynamics at inhibitory synapses, we performed fluorescence time-lapse imaging after photoconversion to directly visualize the exchange kinetics of recombinant Dendra2-gephyrin in cultured spinal cord neurons. Immuno-immobilization of endogenous GlyRs with specific antibodies abolished their lateral diffusion in the plasma membrane, as judged by the lack of fluorescence recovery after photobleaching. Moreover, the cross-linking of GlyRs significantly reduced the exchange of Dendra2-gephyrin compared with control conditions, suggesting that the kinetics of the synaptic gephyrin pool is strongly dependent on GlyR-gephyrin interactions. We did not observe any change in the total synaptic gephyrin levels after GlyR cross-linking, however, indicating that the number of gephyrin molecules at synapses is not primarily dependent on the exchange of GlyR-gephyrin complexes. We further show that our experimental data can be quantitatively accounted for by a model of receptor-scaffold dynamics that includes a tightly interacting receptor-scaffold domain, as well as more loosely bound receptor and scaffold populations that exchange with extrasynaptic pools. The model can make predictions for single-molecule data such as typical dwell times of synaptic proteins. Taken together, our data demonstrate the reciprocal stabilization of GlyRs and gephyrin at inhibitory synapses and provide a quantitative understanding of their dynamic organization.
Published: 2021
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33. NMDARs in Granule Cells contribute to parallel fiber - Purkinje cell synaptic plasticity and motor learning

Author: Guy Bouvier, Antoine Triller, Philippe Rostaing, Martijn Schonewille, Alexandra B. Nelson, Annick Ayon, Caroline Mailhes-Hamon, Allison E. Girasole, Mariano Casado, and Chris I. De Zeeuw
Subjects: Synapse, medicine.anatomical_structure, nervous system, Postsynaptic potential, Synaptic plasticity, Purkinje cell, medicine, NMDA receptor, Parallel fiber, Biology, Motor learning, Receptor, Neuroscience
Abstract: Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic NMDA receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers nitric oxide signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-Purkinje cell (PF-PC) synapses. Consistent with this finding, the selective deletion of GCs NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.Significance StatementLearning depends on synaptic plasticity. The signaling mechanisms that control induction of plasticity determine the learning rules at the specific synapse involved. Moreover, the relationship between the activity patterns of synaptic inputs and the type, direction, and level of plasticity induced may evolve during development. Here, we establish a key link between NMDA receptor activation presynaptic to cerebellar Purkinje cells, downstream signaling mechanisms, and the ability of adult animals to learn a cerebellar motor task.
Published: 2021
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34. NMDARs in granule cells contribute to parallel fiber-Purkinje cell synaptic plasticity and motor learning

Author: M. (martijn) Schonewille, Allison E. Girasole, Philippe Rostaing, Caroline Mailhes-Hamon, Annick Ayon, Alexandra B. Nelson, Antoine Triller, Mariano Casado, C.I. (Chris) de Zeeuw, Guy Bouvier, M. (martijn) Schonewille, Allison E. Girasole, Philippe Rostaing, Caroline Mailhes-Hamon, Annick Ayon, Alexandra B. Nelson, Antoine Triller, Mariano Casado, C.I. (Chris) de Zeeuw, and Guy Bouvier
Abstract: Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic N-methyl-D-aspartate receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers NO signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-PC (PF-PC) synapses. Consistent with this finding, the selective deletion of GC NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.
Published: 2021
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35. Differential homeostatic regulation of glycinergic and GABAergic nanocolumns at mixed inhibitory synapses

Author: Le Corronc H, Pascal Legendre, Antoine Triller, Christian G. Specht, and Xiaojuan Yang
Subjects: Scaffold protein, Gephyrin, biology, Chemistry, biology.protein, Phosphorylation, GABAergic, Endogeny, Channel blocker, Signal transduction, Glycine receptor, Neuroscience
Abstract: Super-resolution imaging of synapses has revealed that key synaptic proteins are dynamically organized within sub-synaptic domains (SSDs). At mixed inhibitory synapses in spinal cord neurons, both GlyRs and GABAARs reside at the same post-synaptic density (PSD). To examine how the different inhibitory receptors are organized and regulated, we carried out dual-color direct stochastic optical reconstruction microscopy (dSTORM). We found that endogenous GlyRs and GABAARs as well as their common scaffold protein gephyrin form SSDs that align with pre-synaptic RIM1/2, thus forming trans-synaptic nanocolumns. Strikingly, GlyRs and GABAARs occupy different sub-synaptic spaces, exhibiting only a partial overlap at mixed inhibitory synapses. When network activity was increased by pharmacological treatment using the K+ channel blocker 4-aminopyridine (4-AP), the GABAAR copy numbers of as well as the number of GABAAR SSDs were reduced, while GlyRs remained largely unchanged. This differential regulation is likely the result of changes in gephyrin phosphorylation that preferentially occurred outside of the SSDs. The total gephyrin content was not altered by 4-AP application. The activity-dependent regulation of GABAARs versus GlyRs suggests that different signaling pathways control their respective sub-synaptic organization. Whereas gephyrin serves as a scaffold protein that upholds GlyR numbers at SSDs, it may act as a switch regulating GABAARs via its phosphorylation state. Taken together, our data reinforce the notion that the precise sub-synaptic organization of GlyRs, GABAARs and gephyrin has functional consequences for the homeostatic regulation of mixed inhibitory synapses.HighlightsAlignment of sub-synaptic domains (SSDs) in trans-synaptic nanocolumns at inhibitory synapses Differential spatial organization of SSDs formed by GlyRs and GABAARs at mixed inhibitory synapses Activity-dependent regulation of GABAARs but not GlyRs at mixed inhibitory synapses Gephyrin phosphorylation is compartmentalized in SSDs within the synaptic scaffold
Published: 2020
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36. Morphologically constrained modeling of spinous inhibition in the somato-sensory cortex

Author: Olivier Gemin, Matteo Fossati, Pablo Serna, Nora Assendorp, Antoine Triller, Cécile Charrier, and Philippe Rostaing
Subjects: medicine.anatomical_structure, Dendritic spine, Synaptic plasticity, Excitatory postsynaptic potential, medicine, Ultrastructure, Sensory cortex, Compartmentalization (psychology), Biology, Somatosensory system, Neuroscience, Calcium signaling
Abstract: Pyramidal neurons are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light-electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 pyramidal neurons of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually-innervated and 38% of inhibitory synapses localized to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.
Published: 2020
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37. Dynamics and organization of proteins in the neuronal plasma membrane

Author: Marianne Renner, Daniel Choquet, Antoine Triller, and Centre National de la Recherche Scientifique (CNRS)
Subjects: Neurons, Pharmacology, 0303 health sciences, Chemistry, [SDV]Life Sciences [q-bio], Cell Membrane, Dynamics (mechanics), Membrane Proteins, 03 medical and health sciences, Cellular and Molecular Neuroscience, Membrane Microdomains, 0302 clinical medicine, Membrane, Biophysics, Animals, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Introductory Journal Article
Abstract: International audience
Published: 2020
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38. Differential Membrane Binding and Seeding of Distinct $\alpha$-Synuclein Fibrillar Polymorphs

Author: Marianne Renner, Virginie Redeker, Luc Bousset, Amulya Nidhi Shrivastava, Ronald Melki, Jimmy Savistchenko, Antoine Triller, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), his work was supported by grants from the EC Joint Programme on Neurodegenerative Diseases ( TransPathND , ANR-17-JPCD-0002-02, ANR-11-IDEX-0001-02 PSL Research University, ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), European Project: (grant No 116060),IMPRiND, European Project: 821522 ,PLASLTINHIB, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), KABANI, Mehdi, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking. - IMPRiND - (grant No 116060) - INCOMING, and Investissement d'avenir - PLASLTINHIB - 821522 - INCOMING
Subjects: Protein subunit, animal diseases, [SDV]Life Sciences [q-bio], Biophysics, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Hippocampus, protein-protein interaction, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, $\alpha$-Synuclein, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Biological neural network, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Receptor, synaptic function, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Synucleinopathies, Neurons, 0303 health sciences, Chemistry, Metabotropic glutamate receptor 5, membrane protein clustering, Articles, nervous system diseases, [SDV] Life Sciences [q-bio], Monomer, Membrane, nervous system, alpha-Synuclein, Membrane binding, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, seeding
Abstract: The aggregation of the protein α-synuclein (α-Syn) leads to different synucleinopathies. We recently showed that structurally distinct fibrillar α-Syn polymorphs trigger either Parkinson’s disease or multiple system atrophy hallmarks in vivo. Here, we establish a structural-molecular basis for these observations. We show that distinct fibrillar α-Syn polymorphs bind to and cluster differentially at the plasma membrane in both primary neuronal cultures and organotypic hippocampal slice cultures from wild-type mice. We demonstrate a polymorph-dependent and concentration-dependent seeding. We show a polymorph-dependent differential synaptic redistribution of α3-Na+/K+-ATPase, GluA2 subunit containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and GluN2B-subunit containing N-methyl-D-aspartate receptors, but not GluA1 subunit containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and metabotropic glutamate receptor 5 receptors. We also demonstrate polymorph-dependent alteration in neuronal network activity upon seeded aggregation of α-Syn. Our findings bring new, to our knowledge, insight into how distinct α-Syn polymorphs differentially bind to and seed monomeric α-Syn aggregation within neurons, thus affecting neuronal homeostasis through the redistribution of synaptic proteins.
Published: 2020
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39. Approaching Protein-Protein Interactions in Membranes Using Single-Particle Tracking and Packing Coefficient Analysis

Author: Marianne Renner and Antoine Triller
Subjects: Membrane, Chemistry, Single-particle tracking, Biophysics, Protein–protein interaction
Published: 2020
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40. Development of Lipid-Coated Semiconductor Nanosensors for Recording of Membrane Potential in Neurons

Author: Shimon Weiss, Gaoling Yang, Dan Oron, Pablo Serna, Omri Bar-Elli, Antoine Triller, Lion Morgenstein, Gloria Ortiz, Asaf Grupi, Evan W. Miller, and Anastasia Ludwig
Subjects: Membrane potential, Materials science, business.industry, Quantum-confined Stark effect, Nanotechnology, 02 engineering and technology, 021001 nanoscience & nanotechnology, 01 natural sciences, Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials, 010309 optics, Semiconductor, Optical imaging, Quantum dot, Nanosensor, 0103 physical sciences, Electrical and Electronic Engineering, 0210 nano-technology, business, Semiconductor Nanoparticles, Biotechnology
Abstract: In the past decade, optical imaging methods have significantly improved our understanding of the information processing principles in the brain. Although many promising tools have been designed, se...
Published: 2020
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41. Inhibitory Receptor Diffusion Dynamics

Author: Antoine Triller and Stephanie A. Maynard
Subjects: 0301 basic medicine, diffusion-trapping, Review, Neurotransmission, Inhibitory postsynaptic potential, Postsynapse, lcsh:RC321-571, inhibitory synapse, 03 medical and health sciences, Cellular and Molecular Neuroscience, Diffusion dynamics, 0302 clinical medicine, Receptor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Molecular Biology, Glycine receptor, Gephyrin, biology, Chemistry, GABAA receptor, gephyrin, 030104 developmental biology, biology.protein, Biophysics, single-particle tracking, glycine receptor, 030217 neurology & neurosurgery, Neuroscience
Abstract: The dynamic modulation of receptor diffusion-trapping at inhibitory synapses is crucial to synaptic transmission, stability, and plasticity. In this review article, we will outline the progression of understanding of receptor diffusion dynamics at the plasma membrane. We will discuss how regulation of reversible trapping of receptor-scaffold interactions in combination with theoretical modeling approaches can be used to quantify these chemical interactions at the postsynapse of living cells.
Published: 2019
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42. Evidence for altered dendritic spine compartmentalization in Alzheimer’s disease and functional effects in a mouse model

Author: Brigitte Potier, Manon Thierry, Benoît Delatour, Alexandre Androuin, Daniel Cattaert, Patrick Dutar, Charles Duyckaerts, Serge Marty, Khalid Hamid El Hachimi, Antoine Triller, Lydia Danglot, U. Valentin Nägerl, Ihsen Youssef, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurobiologie des réseaux (LNR), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'Ecole Normale Supérieure (IBENS), École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire de la Synapse Normale et Pathologique, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Dendritic spine, Dendritic Spines, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Models, Neurological, Hippocampus, Mice, Transgenic, Biology, Presenilin, Membrane Potentials, Pathology and Forensic Medicine, Tissue Culture Techniques, Synapse, Amyloid beta-Protein Precursor, 03 medical and health sciences, Cellular and Molecular Neuroscience, Imaging, Three-Dimensional, 0302 clinical medicine, Alzheimer Disease, Postsynaptic potential, Presenilin-1, Animals, Humans, Computer Simulation, ComputingMilieux_MISCELLANEOUS, Long-term potentiation, Middle Aged, Compartmentalization (psychology), Frontal Lobe, Spine (zoology), Disease Models, Animal, Microscopy, Electron, 030104 developmental biology, Synapses, Female, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Alzheimer's disease (AD) is associated with a progressive loss of synapses and neurons. Studies in animal models indicate that morphological alterations of dendritic spines precede synapse loss, increasing the proportion of large and short ("stubby") spines. Whether similar alterations occur in human patients, and what their functional consequences could be, is not known. We analyzed biopsies from AD patients and APP x presenilin 1 knock-in mice that were previously shown to present a loss of pyramidal neurons in the CA1 area of the hippocampus. We observed that the proportion of stubby spines and the width of spine necks are inversely correlated with synapse density in frontal cortical biopsies from non-AD and AD patients. In mice, the reduction in the density of synapses in the stratum radiatum was preceded by an alteration of spine morphology, with a reduction of their length and an enlargement of their neck. Serial sectioning examined with electron microscopy allowed us to precisely measure spine parameters. Mathematical modeling indicated that the shortening and widening of the necks should alter the electrical compartmentalization of the spines, leading to reduced postsynaptic potentials in spine heads, but not in soma. Accordingly, there was no alteration in basal synaptic transmission, but long-term potentiation and spatial memory were impaired. These results indicate that an alteration of spine morphology could be involved in the early cognitive deficits associated with AD.
Published: 2018
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43. A Simple and Powerful Analysis of Lateral Subdiffusion Using Single Particle Tracking

Author: Antoine Triller, Lili Wang, Laetitia Hennekinne, Sabine Lévi, Marianne Renner, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL-UPMC, Gestionnaire, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: 0301 basic medicine, Anomalous diffusion, Biophysics, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Trapping, Space (mathematics), Thermal diffusivity, Diffusion, Quantitative Biology::Subcellular Processes, 03 medical and health sciences, 0302 clinical medicine, Animals, Statistical physics, Diffusion (business), Simulation, Brownian motion, 030304 developmental biology, Neurons, Physics, 0303 health sciences, Cell Membrane, Biological membrane, Random walk, Single Molecule Imaging, Rats, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Mean squared displacement, 030104 developmental biology, Cell Biophysics, 030217 neurology & neurosurgery
Abstract: In biological membranes many factors such as cytoskeleton, lipid composition, crowding and molecular interactions deviate lateral diffusion from the expected random walks. These factors have different effects on diffusion but act simultaneously so the observed diffusion is a complex mixture of diffusive behaviors (directed, >Brownian, anomalous or confined). Therefore commonly used approaches to quantify diffusion based on averaging of the displacements, such as the mean square displacement, are not adapted to the analysis of this heterogeneity. We introduce a new parameter, the packing coefficient Pc, which gives an estimate of the degree of free movement that a molecule displays in a period of time independently of its global diffusivity. Applying this approach to two different situations (diffusion of a lipid probe and trapping of receptors at synapses), we show that Pc detected and localized temporary changes of diffusive behavior both in time and in space. More importantly, it allowed the detection of periods with very high confinement (~immobility), their frequency and duration, and thus it can be used to calculate the effective kon and koff of scaffolding interactions such those that immobilize receptors at synapses.
Published: 2017
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44. Estradiol modulates the efficacy of synaptic inhibition by decreasing the dwell time of GABA A receptors at inhibitory synapses

Author: Shiva K. Tyagarajan, Yasmine Cantaut-Belarif, Ross A. Cardarelli, Deepak Srivastava, Stephen J. Moss, Jayanta Mukherjee, Antoine Triller, Tarek Z. Deeb, Jamie Maguire, Nicholas J. Brandon, and Menelas N. Pangalos
Subjects: 0301 basic medicine, Multidisciplinary, Gephyrin, biology, GABAA receptor, Hippocampal formation, Neurotransmission, Inhibitory postsynaptic potential, Synapse, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Postsynaptic potential, biology.protein, Excitatory postsynaptic potential, Neuroscience, 030217 neurology & neurosurgery
Abstract: Estrogen plays a critical role in many physiological processes and exerts profound effects on behavior by regulating neuronal excitability. While estrogen has been established to exert effects on dendritic morphology and excitatory neurotransmission its role in regulating neuronal inhibition is poorly understood. Fast synaptic inhibition in the adult brain is mediated by specialized populations of γ-c aA receptors (GABAARs) that are selectively enriched at synapses, a process dependent upon their interaction with the inhibitory scaffold protein gephyrin. Here we have assessed the role that estradiol (E2) plays in regulating the dynamics of GABAARs and stability of inhibitory synapses. Treatment of cultured cortical neurons with E2 reduced the accumulation of GABAARs and gephyrin at inhibitory synapses. However, E2 exposure did not modify the expression of either the total or the plasma membrane GABAARs or gephyrin. Mechanistically, single-particle tracking revealed that E2 treatment selectively reduced the dwell time and thereby decreased the confinement of GABAARs at inhibitory synapses. Consistent with our cell biology measurements, we observed a significant reduction in amplitude of inhibitory synaptic currents in both cultured neurons and hippocampal slices exposed to E2, while their frequency was unaffected. Collectively, our results suggest that acute exposure of neurons to E2 leads to destabilization of GABAARs and gephyrin at inhibitory synapses, leading to reductions in the efficacy of GABAergic inhibition via a postsynaptic mechanism.
Published: 2017
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45. Feasibility analysis of semiconductor voltage nanosensors for neuronal membrane potential sensing

Author: Anastasia Ludwig, Shimon Weiss, Asaf Grupi, Lion Morgenstein, Pablo Serna, Omri Bar-Elli, Antoine Triller, Dan Oron, Gaoling Yang, Evan W. Miller, and Gloria Ortiz
Subjects: Membrane potential, 0303 health sciences, Materials science, business.industry, Nanoparticle, Nanotechnology, 010402 general chemistry, 01 natural sciences, Signal, 0104 chemical sciences, 03 medical and health sciences, Semiconductor, Nanosensor, Temporal resolution, Premovement neuronal activity, business, 030304 developmental biology, Voltage
Abstract: In the last decade, optical imaging methods have significantly improved our understanding of the information processing principles in the brain. Although many promising tools have been designed, sensors of membrane potential are lagging behind the rest. Semiconductor nanoparticles are an attractive alternative to classical voltage indicators, such as voltage-sensitive dyes and proteins. Such nanoparticles exhibit high sensitivity to external electric fields via the quantum-confined Stark effect. Here we report the development of lipid-coated semiconductor voltage-sensitive nanorods (vsNRs) that self-insert into the neuronal membrane. We describe a workflow to detect and process the photoluminescent signal of vsNRs after wide-field time-lapse recordings. We also present data indicating that vsNRs are feasible for sensing membrane potential in neurons at a single-particle level. This shows the potential of vsNRs for detection of neuronal activity with unprecedentedly high spatial and temporal resolution.
Published: 2019
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46. Increased Confinement and Polydispersity of STIM1 and Orai1 after Ca

Author: Xianan, Qin, Lei, Liu, Sang Kwon, Lee, Adolfo, Alsina, Teng, Liu, Chao, Wu, Hojeong, Park, Chenglong, Yu, Hajin, Kim, Jun, Chu, Antoine, Triller, Ben Zhong, Tang, Changbong, Hyeon, Chan Young, Park, and Hyokeun, Park
Subjects: inorganic chemicals, HEK293 Cells, ORAI1 Protein, Cell Membrane, Normal Distribution, Humans, Biological Transport, Calcium, Stromal Interaction Molecule 1, Articles
Abstract: STIM1 (a Ca(2+) sensor in the endoplasmic reticulum (ER) membrane) and Orai1 (a pore-forming subunit of the Ca(2+)-release-activated calcium channel in the plasma membrane) diffuse in the ER membrane and plasma membrane, respectively. Upon depletion of Ca(2+) stores in the ER, STIM1 translocates to the ER-plasma membrane junction and binds Orai1 to trigger store-operated Ca(2+) entry. However, the motion of STIM1 and Orai1 during this process and its roles to Ca(2+) entry is poorly understood. Here, we report real-time tracking of single STIM1 and Orai1 particles in the ER membrane and plasma membrane in living cells before and after Ca(2+) store depletion. We found that the motion of single STIM1 and Orai1 particles exhibits anomalous diffusion both before and after store depletion, and their mobility—measured by the radius of gyration of the trajectories, mean-square displacement, and generalized diffusion coefficient—decreases drastically after store depletion. We also found that the measured displacement distribution is non-Gaussian, and the non-Gaussian parameter drastically increases after store depletion. Detailed analyses and simulations revealed that single STIM1 and Orai1 particles are confined in the compartmentalized membrane both before and after store depletion, and the changes in the motion after store depletion are explained by increased confinement and polydispersity of STIM1-Orai1 complexes formed at the ER-plasma membrane junctions. Further simulations showed that this increase in the confinement and polydispersity after store depletion localizes a rapid increase of Ca(2+) influx, which can facilitate the rapid activation of local Ca(2+) signaling pathways and the efficient replenishing of Ca(2+) store in the ER in store-operated Ca(2+) entry.
Published: 2019

47. SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity

Author: Philippe Isope, Oana Vigy, Célia Bosso-Lefèvre, Andréa Dumoulin, Mélanie Albert, Fernando A Giuliani, Jean-Louis Bessereau, Inés González-Calvo, Sylvana Tahraoui, Séverine M. Sigoillot, Anouar Khayachi, Maxime Veleanu, Mélanie Carquin, Keerthana Iyer, Yann Nadjar, Martial Séveno, Laure Rondi-Reig, Antoine Triller, Fekrije Selimi, and Jean Vincent
Subjects: 0303 health sciences, biology, Protein subunit, NEDD4, AMPA receptor, Transmembrane protein, Motor coordination, 03 medical and health sciences, 0302 clinical medicine, Proteostasis, Ubiquitin, Synaptic plasticity, biology.protein, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SummaryAt excitatory synapses, the choice between recycling or degradation of glutamate AMPA receptors controls the direction of synaptic plasticity. In this context, how the degradation machinery is targeted to specific synaptic substrates in an activity-dependent manner is not understood. Here we show that SUSD4, a complement-related transmembrane protein, is a tether for HECT ubiquitin ligases of the NEDD4 subfamily, which promote the degradation of a large number of cellular substrates. SUSD4 is expressed by many neuronal populations starting at the time of synapse formation. Loss-of-function ofSusd4in the mouse prevents activity-dependent degradation of the GLUA2 AMPA receptor subunit and long-term depression at cerebellar synapses, and leads to impairment in motor coordination adaptation and learning. SUSD4 could thus act as an adaptor targeting NEDD4 ubiquitin ligases to AMPA receptors during long-term synaptic plasticity. These findings shed light on the potential contribution ofSUSD4mutations to the etiology of neurodevelopmental diseases.
Published: 2019
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48. Cell biology and dynamics of Neuronal Na+/K+-ATPase in health and diseases

Author: Amulya Nidhi Shrivastava, Antoine Triller, Ronald Melki, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), KABANI, Mehdi, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: 0301 basic medicine, Pharmacology, Parkinson's disease, Chemistry, Alternating hemiplegia of childhood, Neurodegeneration, SOD1, Neuronal membrane, medicine.disease, 3. Good health, Cell biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Expression pattern, Lateral diffusion, medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Na+/K+-ATPase, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract: Neuronal Na+/K+-ATPase is responsible for the maintenance of ionic gradient across plasma membrane. In doing so, in a healthy brain, Na+/K+-ATPase activity accounts for nearly half of total brain energy consumption. The α3-subunit containing Na+/K+-ATPase expression is restricted to neurons. Heterozygous mutations within α3-subunit leads to Rapid-onset Dystonia Parkinsonism, Alternating Hemiplegia of Childhood and other neurological and neuropsychiatric disorders. Additionally, proteins such as α-synuclein, amyloid-β, tau and SOD1 whose aggregation is associated to neurodegenerative diseases directly bind and impair α3-Na+/K+-ATPase activity. The review will provide a summary of neuronal α3-Na+/K+-ATPase functional properties, expression pattern, protein-protein interactions at the plasma membrane, biophysical properties (distribution and lateral diffusion). Lastly, the role of α3-Na+/K+-ATPase in neurological and neurodegenerative disorders will be discussed. This article is part of the special issue entitled ‘Mobility and trafficking of neuronal membrane proteins’.
Published: 2018
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49. Small fluorescence-activating and absorption-shifting tag for tunable protein imaging in vivo

Author: Jérôme Quérard, Frederico M. Pimenta, Nelly Morellet, Julien Rossignol, Sophie Vriz, Ewen Lescop, Carole Gauron, Yong Chen, Michel Volovitch, Thomas Le Saux, Sylvie Maurin, Christian G. Specht, Arnaud Gautier, Ludovic Jullien, Marie-Aude Plamont, Antoine Triller, Buyan Pan, Jian Shi, Emmanuelle Billon-Denis, Karine Moncoq, HAL-UPMC, Gestionnaire, Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Embryo, Nonmammalian, Cell Survival, Recombinant Fusion Proteins, Protein tag, Yeast display, Corrections, Fluorescence, Green fluorescent protein, 03 medical and health sciences, Imaging, Three-Dimensional, fluorescence imaging, [CHIM] Chemical Sciences, Organelle, Animals, Humans, [CHIM]Chemical Sciences, directed evolution, Zebrafish, Multidisciplinary, Staining and Labeling, Chemistry, Absorption, Radiation, Cell sorting, Ligand (biochemistry), Directed evolution, fluorogenic ligand, 030104 developmental biology, Biochemistry, Physical Sciences, Biophysics, Genetic Engineering, HeLa Cells, Subcellular Fractions
Abstract: International audience; This paper presents Yellow Fluorescence-Activating and absorption-Shifting Tag (Y-FAST), a small monomeric protein tag, half as large as the green fluorescent protein, enabling fluorescent labeling of proteins in a reversible and specific manner through the reversible binding and activation of a cell-permeant and nontoxic fluorogenic ligand (a so-called fluorogen). A unique fluorogen activation mechanism based on two spectroscopic changes, increase of fluorescence quantum yield and absorption red shift, provides high labeling selectivity. Y-FAST was engineered from the 14-kDa photoactive yellow protein by directed evolution using yeast display and fluorescence-activated cell sorting. Y-FAST is as bright as common fluorescent proteins, exhibits good photostability, and allows the efficient labeling of proteins in various organelles and hosts. Upon fluorogen binding, fluorescence appears instantaneously, allowing monitoring of rapid processes in near real time. Y-FAST distinguishes itself from other tagging systems because the fluorogen binding is highly dynamic and fully reversible, which enables rapid labeling and unlabeling of proteins by addition and withdrawal of the fluorogen, opening new exciting prospects for the development of multiplexing imaging protocols based on sequential labeling.
Published: 2015
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50. Les faits sont têtus

Author: Antoine Triller and Michèle Leduc
Subjects: General Engineering
Published: 2020
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