Les synapses : Complexité et Diversité / Synapses: from complexity to diversity

Séminaire organisé par Jean-Louis Bessereau (Institut Neuromyogène (Univ. Claude Bernard Lyon 1) et Fekrije Selimi (CIRB, Collège de France) du 14 au 19 mai 2018

Participants

Jean-Louis Bessereau, Thomas Biederer, Kendal Broadie, Nils Brose, Melissa Cizeron, Joris De Wit, Cagla Eroglu-Bagnat, Csaba Földy, Seth Grant, Etienne Herzog, Bérangère Pinan-Lucarré, Erin Schuman, Fekrije Selimi, Kang Shen, Séverine Sigoillot, Scott Soderling, Olivier Thoumine, Antoine Triller, Dan Ohtan Wang, Mei Zhen
Agathe Franck (Cercle FSER) pour l’animation du Meeting Scientifique Ouvert au Public (MSOP)

Résumé

Les synapses sont les éléments constitutifs du cerveau : leur formation et leur fonction correctes sont à la base des processus cognitifs. Selon l’Organisation Mondiale de la Santé, les troubles mentaux touchent 10 à 20% des enfants et des adolescents dans le monde et sont la principale cause d’invalidité chez les jeunes. Les anomalies synaptiques sont au centre de nombreux troubles mentaux tels que l’autisme ou la schizophrénie. Les résultats scientifiques de ces dernières années ont montré la complexité moléculaire des synapses avec l’identification de milliers de protéines synaptiques différentes. Pourtant, la signification de cette complexité n’est pas comprise. Alors que de récentes technologies ont montré la diversité morphologique et fonctionnelle des synapses, leur diversité moléculaire et sa signification fonctionnelle restent à décrire. Le séminaire des Treilles qui a eu lieu du 14 au 19 Mai a permis d’échanger différentes approches et résultats qui vont permettre d’aborder ces questions. Ce séminaire a permis d’ouvrir sur de nouveaux horizons scientifiques et de mettre en place de nouvelles collaborations. S’attaquer à ce nouveau défi dans notre domaine aura une grande influence sur notre compréhension de la fonction cérébrale et de la maladie.

Compte-rendu (en anglais)

The first session of the meeting dealt with the molecular diversity of synapses and the different types of regulation that can lead to this diversity. Seth Grant (University of Edinburgh) presented his work on the “synaptome mapping” describing the diversity of synapse types in the brain using a combination of biochemical and imaging approaches. Melissa Cizeron (University of Edinburgh, junior scientist) showed how imaging of tagged synaptic scaffolding proteins in the brain during the lifespan of the mouse reveals the specific developmental trajectories for synapses in different brain regions. Characterization of turning points, i.e. time-points when the trajectory changes direction, showed differences between brain regions and sub-regions. Finally, network analysis of synapse parameters indicated that the highest level of dissimilarity between different brain regions occurs in young adult mice. Erin Schuman (Max Planck Institute for Brain Research) showed the complexity of the local transcriptome at synapses and of the regulation of its translation, as well as new technologies to study these processes. She described recent work showing that a large fraction of axon terminals from the mature mouse brain contain mRNA and translational machinery and actively translate proteins. Furthermore, recent advances in the analysis of presynaptic transcriptome and cell type specific proteomics were discussed. Dan Ohtan Wang (Kyoto University) described epitranscriptomics, a potential new level of regulation of the molecular diversity of synapses. Her lab found N6-methyl-adenosine(m6A), an abundant internal mRNA modification in mammals, on thousands of synaptosomal RNA species. The protein coding capacity of the modified mRNA is not affected by this modification but the stability and translation efficiency have been shown to be altered in multiple biological contexts. She demonstrated that disrupting m6A recognition by reader proteins results in synaptic dysfunction. Scott Soderling (Duke University) described the loss of signal filtering in synapses of Arp2/3 knockout mice, as well as new technologies to study the molecular complexity of synapses based on chemogenetics and Crispr/Cas9. Fekrije Selimi (Collège de France) and Séverine Sigoillot (Collège de France, junior scientist) described their studies of the molecular diversity of excitatory synapses. Using synapse-specific protein profiling and neuron-specific transcriptomics in vivo, they have started to decipher the molecular code underlying the specific identity of the two excitatory synapse types on cerebellar Purkinje cells. They also described a new molecular mechanism allowing the specific regulation of AMPA receptor turnover at synapses, with implications for synapse physiology and behavior.

The second session discussed the presynapse. Etienne Herzog (CNRS – Université de Bordeaux) described how the FASS technology allows sorting of specific synaptosomes from the mouse brain to analyze their diverse composition using proteomics and imaging. Nils Brose (Max Planck Institute for Experimental Medicine) presented his work on the dynamic control of the synaptic vesicle priming machinery and its role in short-term synaptic plasticity. His presentation highlighted the emerging view that the activity-dependent control of Munc13-family synaptic vesicle priming proteins by convergent second messenger pathways equips different synapses with distinct plasticity features. These plasticity features, in turn, determine key computational characteristics of the corresponding synapses and nerve cells, which are thought to be of key relevance for many brain functions, including sensory adaptation, gain control, and memory. Kang Shen (Stanford University) described the role of the THO nuclear export complex as a master regulator of presynaptic development in C. elegans and mouse.

The third session aimed at discussing extracellular factors and how they shape the synapse. Kendal Broadie (Vanderbilt University) presented work on a wide range of key extracellular regulators of synaptogenesis discovered by genetic dissection at the Drosophila neuromuscular junction. These include secreted glycan-binding lectins, heparan sulfate proteoglycans, matrix metalloproteinases, and their extracellular regulators. These secreted proteins control trans-synaptic signaling via Wnt, BMP and Jeb-Alk pathways to modulate synaptic functional differentiation and sculpt synaptic architecture. Cagla Eroglu (Duke University) presented her studies of the molecular mechanisms underlying the synaptogenic role of glial cells, in particular astrocytes, during development. Jean-Louis Bessereau (Institut Neuromyogène) and Bérangère Pinan-Lucarré (Institut Neuromyogène, junior scientist) presented their work on the molecular mechanisms regulating synaptic specification and development at the neuromuscular junctions of C. elegans. They showed that Punctin, a neurally-secreted matricellular protein, is an anterograde synaptic organizer, which governs local assembly of both extracellular and intracellular scaffolding complexes at excitatory and inhibitory synapses.

The fourth session dealt with dynamics at the synapse. Antoine Triller (Ecole Normale Supérieure) described his work on the dynamic synapse, in particular the diffusion properties of receptors and their regulation by several factors, in particular calcium, radixin and microglia. Olivier Thoumine (CNRS-Université of Bordeaux) presented his studies on the dynamics of neurexin/neuroligin interactions probed by single molecule imaging, and on the regulation of post-synaptic differentiation by neuroligin-1 tyrosine phosphorylation, using a combination of electrophysiology and optogenetic stimulation.

The fifth session addressed the mechanisms controlling synapse development Thomas Biederer (Tufts University) described his studies of region-specific roles of synaptic organizers in the cortex. His talk highlighted the functional cooperation of trans-synaptic organizers, presenting novel findings that synaptic adhesion molecules from different gene families can work together to control excitatory synaptic connectivity in the prefrontal cortex. In addition, Dr. Biederer presented results that the immunoglobulin protein SynCAM 1 acts in the visual cortex to control the closure of the critical period in the visual system during which the cortex remains plastic. These findings can impact future work on aberrations underlying developmental disorders. Joris de Wit (VIB Center for Brain & Disease Research, KU Leuven) presented his work on the trafficking and intraneuronal sorting of the adhesion molecule neurexin-1, a major organizing molecule of presynaptic function that has been linked to autism and schizophrenia. Using a combination of proteomics, molecular and cellular approaches as well as live-cell imaging, his lab found that neurexin-1 takes a round-about trafficking route to the presynaptic terminal. In the absence of SorCS1-mediated sorting, presynaptic function is impaired. This work reveals a new mechanism by which neurons control the molecular composition of synapses. Csaba Földy (University of Zurich) described his research on single cell gene expression, and how adhesion molecule isoforms identify cell types and their developmental origin. Mei Zhen (Lunenfeld-Tanenbaum Research Institute) described the pipeline established by her laboratory and her collaborators for high quality resolution EM reconstruction of the neuronal circuits in Caenorhabditis elegans.