Nanoskalige Signaturen in der Organisation synaptischer Diversität
Zusammenfassung der Projektergebnisse
Synapses are highly specialized structures transferring information between neurons, and are thought to be cellular substrates for learning and memory. One hallmark of synapses is their functional heterogeneity. Indeed, synapses can exhibit high or low transmission fidelity, and this diversity results in synapse-specific differences in response fluctuation and short-term plasticity. Functional synaptic diversity is critical for routing and encoding sensory information in the brain. Yet, the molecular mechanisms defining such diversity remain unexplored. Following Ca2+ influx through Voltage Gated Ca2+ channels (VGCCs), synaptic vesicles (SVs) fuse at the presynaptic active zones (AZs). Within this project we hypothesized that nanoscale variations in the number and location of active zone (AZ) scaffold proteins relative to VGCCs, as well as synapse-specific expression of the molecular machinery controlling synaptic vesicle (SV) fusion, might determine differences in coupling distances between VGCCs and SVs and thereby functional synaptic diversity. Before the funding period of NanoSYNDIV, we already started to focus our work on differential nanoscopic organization and synapse diversity of the presynaptic active zone. We, funded by other means, addressed the role of RBP2 in synapse diversity at murine hippocampal CA3-CA1 (tightly coupled) versus MF-CA3 synapses (loosely coupled). Our results provided a coherent mechanistic understanding on how RBP2 tunes coupling distances and synaptic release properties by differentially modulating the levels of the release factor Munc13-1 at MF-CA3 versus CA3-CA1 synapses. Moreover, our results showed that RBP2 selectively impacts on MF neurotransmitter release by promoting SV docking and priming via stabilization of Munc13-1. We could also demonstrate that Unc13A and Unc13B, the two isoforms of the release factor (M)Unc13, differentially tune synaptic short term plasticity by setting coupling diversity. We showed that two orthogonal scaffold proteins (ELKS family Bruchpilot, BRP, and Syd-1) cluster specific (M)Unc13 release factor isoforms either close (BRP/Unc13A) or further away (Syd-1/Unc13B) from VGCCs across synapses of the Drosophila olfactory system. Notably, the levels of these two “modules” varied between different synapse types thereby tuning release features. Additionally, funded by other means, we demonstrated that Unc13A and Unc13B play distinct roles in neural decoding of olfactory information at excitatory projection neuron (ePN) output synapses. Indeed, reduction of Unc13A levels in ePNs attenuates responses to both aversive and appetitive stimuli, while Unc13B knock-down provokes a general shift towards appetitive values. Collectively, we provided direct genetic evidence that release components defining distinct nanoscopic coupling distances differentially control STP to play distinct roles in neural decoding of sensory information at behavioural level. Our work financed via NanoSYNDIV lead to the identification of the evolutionary conserved complex of Spinophilin with its antagonist Syd-1. We found that this complex controls Unc13A accumulation at Kenyon cells synapses in the mushroom body within the temporal extended consolidation of mid-term memories. This work is a natural extension of NanoSYNDIV for the fact that Syd-1 controls the Unc13A/B ratio in the development of Drosophila brain synapse diversity. Altogether, our work steered presynaptic research in direction of relevant molecular players and structural principles defining synapse molecular and functional diversity.
Projektbezogene Publikationen (Auswahl)
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Active Zone Scaffold Protein Ratios Tune Functional Diversity across Brain Synapses. Cell Reports, 23(5), 1259-1274.
Fulterer, Andreas; Andlauer, Till F.M.; Ender, Anatoli; Maglione, Marta; Eyring, Katherine; Woitkuhn, Jennifer; Lehmann, Martin; Matkovic-Rachid, Tanja; Geiger, Joerg R.P.; Walter, Alexander M.; Nagel, Katherine I. & Sigrist, Stephan J.
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RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses. eLife, 8.
Brockmann, Marisa M.; Maglione, Marta; Willmes, Claudia G.; Stumpf, Alexander; Bouazza, Boris A.; Velasquez, Laura M.; Grauel, M. Katharina; Beed, Prateep; Lehmann, Martin; Gimber, Niclas; Schmoranzer, Jan; Sigrist, Stephan J.; Rosenmund, Christian & Schmitz, Dietmar
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Unc13A and Unc13B contribute to the decoding of distinct sensory information in Drosophila. Nature Communications, 12(1).
Pooryasin, Atefeh; Maglione, Marta; Schubert, Marco; Matkovic-Rachid, Tanja; Hasheminasab, Sayed-mohammad; Pech, Ulrike; Fiala, André; Mielke, Thorsten & Sigrist, Stephan J.
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An antagonism between Spinophilin and Syd-1 operates upstream of memory-promoting presynaptic long-term plasticity. eLife, 12.
Ramesh, Niraja; Escher, Marc; Turrel, Oriane; Lützkendorf, Janine; Matkovic, Tanja; Liu, Fan & Sigrist, Stephan J.
