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Talk abstractsJean-Louis Bessereau (U Lyon) TBA
Dilja Krueger-Burg (U Mainz) Abnormalities in the balance of excitatory to inhibitory neurotransmission have been proposed to play a key role in the etiology of psychiatric and neurodevelopmental disorders, and substantial evidence links mutations in the proteins that mediates excitatory synaptic transmission to these disorders. In contrast, the role of alterations in the molecular machinery at inhibitory synapses has received surprisingly little attention. In recent years, however, an increasing number of variants in GABAergic postsynaptic proteins has been identified in patients with mental or neurodevelopmental disorders, highlighting the urgent need for a better understanding of the involvement of these proteins in health and disease. Here I present recent studies on the molecular mechanisms by which the prototypical GABAergic synaptic adhesion protein Neuroligin-2 and its interaction partners regulate behavioral circuits in mouse models. In particular, I focus on a key theme that emerges from these studies, i.e. the importance of GABAergic synapse diversity in understanding the consequences of mutations in these proteins on behavioral output. The GABAergic inhibitory system is highly heterogeneous, with a large number of neuronal subtypes contributing vastly different functions to neuronal information processing, and recent evidence indicates that this cellular diversity is accompanied by a corresponding molecular diversity at GABAergic synapses. By identifying synapse- and circuit-specific functions of individual GABAergic postsynaptic proteins, it may not only be possible to better understand their role in the pathogenesis of psychiatric and neurodevelopmental disorders, but also to develop circuit-specific therapeutic approaches with improved selectivity for the targeted behavioral symptoms.
Matthieu Letellier (U Bordeaux) Decades of pharmacological, physiological, and neurochemical research have revealed synapse diversity, classifying synapses as excitatory or inhibitory and associating them with specific neurotransmitter systems. More recent studies reveal even greater diversity within each type, with synapses varying in structure, strength, and molecular composition in function of neuronal activity. Our lab explores synapse diversity by examining how neurons distinguish among their inputs to build specialized postsynaptic domains. What molecular cues enable the postsynaptic neuron to match diverse inputs with the appropriate scaffolding proteins, receptors, and signaling molecules? My presentation will have two parts. First, I will discuss the role of the postsynaptic cell adhesion molecule neuroligin-1 in the specific assembly and plasticity of excitatory synapses, highlighting our effort to manipulate and visualize the endogenous protein. I will show evidence for a tyrosine phosphorylation switch that prevents NLGN1 from interacting with gephyrin, facilitating the specific recruitment of the scaffolding protein PSD-95 and AMPA receptors (AMPARs) aligned with glutamate release sites. I will discuss the impact of this mechanism in the regulation of the excitation-inhibition balance and input-specific long-term potentiation. Second, I will highlight an activity-dependent synaptic tagging mechanism in which the spine apparatus related protein synaptopodin acts as a “synaptic tag” whose translation at some synapses, but not others, is locally controlled by miR-124, a brain-enriched microRNA. Local expression of synaptopodin promotes the “capture” of surface-diffusing AMPA receptors and spine growth to support non-uniform and input-specific synaptic plasticity. Our findings underscore that synapses are heterogeneous not only in structure and function but also in their capacity for plasticity.
Hans Maric (U Würzburg) Neuronal transmission is fundamental to normal brain function, supporting learning, memory, and cognitive processing. Intracellular scaffolds play a crucial role in ensuring effective transmission by mediating the precise formation, regulation, and function of synapses through direct interactions with receptors and channels. However, the detailed molecular mechanisms by which these scaffolds organize synaptic components and maintain synapse size and signaling efficacy remain to be fully elucidated.
This presentation will highlight our insights into the molecular interactions that shape synaptic architecture, focusing on gephyrin at inhibitory synapses, PSD-95 at excitatory sites, and ankyrin at the axon initial segment and dendrites. In vitro studies, including broad interactor screening, high-throughput mapping, and interaction profiling, identified binding hierarchies, sequence requirements and membrane protein competition. Building on these insights, we started to develop fluorescent probes for improved scaffold visualization but also the quantification of the fractional occupancy and function of distinct scaffold sites. We envision the use of these probes as tools for resolving and quantifying the fundamental processes underlying synapse formation, stability, and regulation and further probing the neuropharmacological potential of targeting specific interaction sites.
Overall, this presentation provides a molecular perspective on synapse regulation through scaffold interactions and introducing novel activity-based synthetic fluorescent probes.
Jonas Ranft (ENS-PSL, Paris) Synaptic strength is the key determinant for network function and is thought to underlie learning and memory. A rough proxy for synapse strength is the size of the postsynaptic domain, which is largely constituted of scaffold proteins that provide binding sites for neurotransmitter receptors. Yet how exactly postsynaptic domain size is regulated or maintained remains unclear, not least because domains of both excitatory and inhibitory synapses are highly dynamic structures with a constant exchange between intra- and extrasynaptic pools. In this talk, I will present our efforts to contribute to these questions from a modeling perspective, by proposing quantitative biophysical models of the dynamics of receptors and scaffold proteins at inhibitory synapses. In particular, we quantitatively characterized receptor and scaffold protein kinetics at glycinergic synapses by combining advanced imaging techniques with a quantitative model of postsynaptic formation and maintenance. Our results highlight the importance of receptor-scaffold interactions for stable synaptic receptor copy numbers. More generally, our work shows how hypothesis-driven modeling can drive new prediction-driven experiments, which in turn allow us to refine our theoretical understanding of underlying processes.
Marianne Renner (Sorbonne U & IFM, Paris) Single particle tracking experiments suggest that the interactions receptor/scaffold responsible for the immobilization of receptors in synapses are rather weak in the real conditions of the post-synaptic membrane. In addition, lateral diffusion is strongly impaired in the post-synaptic membrane due to molecular crowding, which could be in part generated by immobile receptors themselves. To analyze how the distribution of scaffolding molecules and receptor’s self-crowding affect the capture of new receptors, we set particle-based Monte Carlo simulations. Results show that depending on the distribution of scaffolding molecules, crowding can help to stabilize synapses by enhancing receptor-scaffold interaction and reducing the capture of new molecules. The distribution of scaffolding sites in several nano-clusters reduced crowding and fostered the exchange of molecules accelerating synaptic plasticity. Synapses could switch between two regimes, becoming more stable or more plastic depending on the internal distribution of molecules.
Christian Specht (UPSaclay, Le Kremlin-Bicêtre) Single molecule localisation microscopy (SMLM) makes it possible to study the precise organisation of small cellular compartments such as synapses. Beyond super-resolution analysis, SMLM can provide quantitative information by converting the numbers of fluorophore detections into molecule numbers. Here, I present recent data about the organisation of glycine receptors (GlyRs) and GABAA receptors at inhibitory synapses in the mouse CNS. Our results show that GlyRs are clustered at high densities of around 2000 receptor complexes per µm2 at inhibitory synapses in the spinal cord independent of synapse size. This suggests that the GlyR complexes are assembled in a stereotypic manner at glycinergic synapses across the spinal cord. The situation is very different in the hippocampus, were inhibitory synapses mostly contain GABAARs. Thanks to the sensitivity of SMLM, however, we could also identify low copy GlyRs at these synapses. Together, our data point to the existence of a continuum of inhibitory synapse types from purely GABAergic to purely glycinergic compositions.
Tatjana Tchumatchenko (U Bonn) In neurons, the quantities of mRNAs and proteins are traditionally assumed to be determined by functional, electrical or genetic factors. Yet, there may also be global, currently unknown computational rules that are valid across different molecular species inside a cell. Surprisingly, our results show that the energy for molecular turnover is a significant cellular expense, en par with spiking cost, and which requires energy-saving strategies. We show that the drive to save energy determines transcript quantities and their location while acting differently on each molecular species depending on the length, longevity and other features of the respective molecule.
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