Synaptic Plasticity and Super-Resolution Microscopy
Team Leader : Valentin Nägerl
Valentin Nägerl is a full professor of neuroscience and bio-imaging at the University of Bordeaux and a senior member of the 'Institut Universitaire de France' (IUF). He also directs the research group 'Synaptic Plasticity and Super-Resolution Microcopy' at the Interdisciplinary Institute for NeuroScience of the CNRS / University of Bordeaux.
The biology of synapses is an extremely productive and interdisciplinary scientific endeavor, harboring central questions of cell biology and neuroscience. Synapses are physical sites of intercellular contact that transmit and transform information in a very rapid and flexible way, playing a pivotal role for learning and memory formation as well as neurological diseases of the mammalian brain. Since synapses are tiny and densely packed in light-scattering brain tissue, understanding their dynamic behavior in mechanistic terms under physiological conditions is a serious experimental challenge. Fortunately, recent technological innovations, particularly in labeling and live-cell imaging techniques, are helping to break new ground. The advent of fluorescence microscopy beyond the diffraction limit has opened up huge experimental opportunities to directly image and resolve key physiological signaling events inside single synapses in intact brain tissue, a possibility which was considered a pipe dream until recently. Our group is invested in harnessing these exciting technological developments to study synapses in their natural habitat and under realistic conditions, aiming to better understand higher brain function and disorders in terms of the underlying synaptic mechanisms.
To this end, we are developing and applying novel super-resolution microscopy approaches (STED microscopy), giving us a much more complete and refined view of the dynamic behavior and plasticity of neuronal synapses and their interactions with glia cells inside living brain slices and in the intact mouse brain in vivo. Recently, we invented super-resolution shadow imaging (SUSHI), a new technique to visualize the extracellular space of the brain (ECS), which is an important, however understudied, compartment for neural signaling and brain homeostasis. These approaches are complemented by a combination of 2-photon imaging & photoactivation and patch-clamp electrophysiology aided by tools from molecular genetics.
Astrocytes: up close & personal via STED microscopy
Structural basis of astrocytic Ca2+ signals at tripartite synapses
Astrocytic Ca2+ signals can be fast and local, supporting the idea that astrocytes have the ability to regulate single synapses. However, the anatomical basis of such specific signaling remains unclear, owing to difficulties in resolving the spongiform domain of astrocytes where most tripartite synapses are located. Using 3D-STED microscopy in living organotypic brain slices, we imaged the spongiform domain of astrocytes and observed a reticular meshwork of nodes and shafts that often formed loop-like structures. These anatomical features were also observed in acute hippocampal slices and in barrel cortex in vivo. The majority of dendritic spines were contacted by nodes and their sizes were correlated. FRAP experiments and Ca2+ imaging showed that nodes were biochemical compartments and Ca2+ microdomains. Mapping astrocytic Ca2+ signals onto STED images of nodes and dendritic spines showed they were associated with individual synapses. Here, we report on living nanoscale organization of astrocytes, identifying nodes as a functional astrocytic component of tripartite synapses that may enable synapse-specific communication between neurons and astrocytes.
The study (Arizono et al, Nature Communications 2020), which was spearheaded by Misa Arizono in the Nägerl team, was supported by a long-standing and fruitful collaboration with the Bordeaux Neurocampus teams of Marsicano and Oliet, which received funding from the Labex Brain and ANR.
Authors: Misa Arizono, V. V. G. Krishna Inavalli, Aude Panatier, Thomas Pfeiffer, Julie Angibaud, Florian Levet, Mirelle J. T. Ter Veer, Jillian Stobart, Luigi Bellocchio, Katsuhiko Mikoshiba, Giovanni Marsicano, Bruno Weber, Stéphane H. R. Oliet & U. Valentin Nägerl
- See the publication on Nature Communications volume 11, Article number: 1906 (2020) https://www.nature.com/articles/s41467-020-15648-4
- Contact: Valentin Nägerl, IINS
Salivary Gland Surveillance - Science Immunology, April 2020
Salivary gland macrophages and tissue-resident CD8+ T cells cooperate for homeostatic organ surveillance
Pathogen sensing in tissues is critical to generating rapid immune responses. Within these tissues, macrophages and resident memory CD8+ T cells (TRM) work together to detect pathogens, and Stolp et al. use intravital imaging of submandibular salivary glands (SMG) to show that TRM follow tissue macrophage topology in a dynamic manner. Macrophage depletion is associated with reduced TRM motility and a diminished clustering in response to inflammatory chemokines. However, although SMG TRM respond to chemoattractants, autonomous motility is also observed and is mediated by friction and insertion of cellular protrusions into microenvironmental gaps. These findings demonstrate that SMG TRM can use different motility modes in proximity to tissue macrophages to patrol the tissue microenvironment.
Authors: Bettina Stolp, Flavian Thelen, Xenia Ficht, Lukas M. Altenburger, Nora Ruef, V. V. G. Krishna Inavalli, Philipp Germann, Nicolas Page, Federica Moalli, Andrea Raimondi, Kirsten A. Keyser, S. Morteza Seyed Jafari, Francesca Barone, Matthias S. Dettmer, Doron Merkler, Matteo Iannacone, James Sharpe, Christoph Schlapbach, Oliver T. Fackler, U. Valentin Nägerl and Jens V. Stein
- See the publication on Science Immunology 03 Apr 2020: Vol. 5, Issue 46, eaaz4371 - DOI: 10.1126/sciimmunol.aaz4371
- Contact: Valentin Nägerl, IINS
Nanoscale remodeling of astroglial processes - Neuron, Sept. 2020
LTP induction boosts glutamate spillover by driving withdrawal of perisynaptic astroglia
Extrasynaptic actions of glutamate are limited by high-affinity transporters expressed by perisynaptic astroglial processes (PAPs): this helps maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodeling, but how this affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here, we used advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses. Optical glutamate sensors combined with patch-clamp and 3D molecular localization reveal that LTP induction thus prompts spatial retreat of astroglial glutamate transporters, boosting glutamate spillover and NMDA-receptor-mediated inter-synaptic cross-talk. The LTP-triggered PAP withdrawal involves NKCC1 transporters and the actin-controlling protein cofilin but does not depend on major Ca2+-dependent cascades in astrocytes. We have therefore uncovered a mechanism by which a memory trace at one synapse could alter signal handling by multiple neighboring connections.
Authors: Christian Henneberger*, Lucie Bard*, Aude Panatier*, James P. Reynolds*, Olga Kopach*, Nikolay I. Medvedev*, Daniel Minge*, Michel K. Herde, Stefanie Anders, Igor Kraev, Janosch P. Heller, Sylvain Rama, Kaiyu Zheng, Thomas P. Jensen, Inmaculada Sanchez-Romero, Colin J. Jackson, Harald Janovjak, Ole Petter Ottersen, Erlend Arnulf Nagelhus, Stephane H.R. Oliet, Michael G. Stewart#, U. Valentin Nägerl#, Dmitri A. Rusakov#
* Co-first authors, #Co-corresponding authors
This was a collaborative study with Christian Henneberger (Univ. of Bonn), Dmitri Rusakov (UCL) and Aude Panatier, Stéphane Oliet and Valentin Nägerl as partners in Bordeaux.
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