Jean-Louis Bessereau (organiser), 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 (organiser), Kang Shen, Séverine Sigoillot, Scott Soderling, Olivier Thoumine, Antoine Triller, Dan Ohtan Wang, Mei Zhen
And Agathe Franck (Cercle FSER) for the “Scientific Meeting Open to the Public”
by Jean-Louis Bessereau and Fekrije Selimi
14 – 19 May, 2018
Synapses are the key signaling units in the brain, and their proper formation and function is the basis of all brain outputs, from simple movements to cognition and emotions. Recent progress in nerve cell biology and neurogenetics, with the identification of thousands of different synapse-specific proteins, revealed a massive complexity of synapses. However, the functional significance of this complexity is not understood.
Nervous systems, even in relatively simple organisms such as the fruit fly or the nematode worm Caenorhabditis elegans, are built of different types of neurons that are connected through synapses with specific morphological and functional characteristics. Thus, synapses are intrinsically diverse to serve different functional purposes. But to what extent is the molecular complement of a specific synapse type different from other synapses, what are the molecular determinants that characterize each synapse type, and how do they control synapse formation and the development of a functional nervous system?
The meeting organized at les Treilles on May 14th till May 19th, 2018, gathered neurobiologists, including three young scientists, that study these questions using innovative approaches and different model organisms, ranging from flies and worms to mammals. The presentations and discussions highlighted (i) the complementarity of the different approaches developed to tackle the molecular and functional diversity of synapses (imaging, single cell transcriptomics, synaptosome and synapse specific proteomics), (ii) important insights brought by studying the molecular and functional diversity of synapses in different model organisms, and (iii) new cell biological mechanisms that control the molecular diversity of synapses. Overall, the intense exchanges at les Treilles led to the formation of new collaborations between scientists present and reinforced the idea that a precise analysis of the different synapse types, their molecular composition and functional features is a key requirement in the era of brain connectomics.
Keywords: Synapse; Specificity; Molecular Diversity; Genetics; Development;
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.