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Dive into the research topics where Wernher Fouquet is active.

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Featured researches published by Wernher Fouquet.


Science | 2006

Bruchpilot Promotes Active Zone Assembly, Ca2+ Channel Clustering, and Vesicle Release

Robert J. Kittel; Carolin Wichmann; Tobias M. Rasse; Wernher Fouquet; Manuela Schmidt; Andreas Schmid; Dhananjay A. Wagh; Christian Pawlu; Robert Kellner; Katrin I. Willig; Stefan W. Hell; Erich Buchner; Manfred Heckmann; Stephan J. Sigrist

The molecular organization of presynaptic active zones during calcium influx–triggered neurotransmitter release is the focus of intense investigation. The Drosophila coiled-coil domain protein Bruchpilot (BRP) was observed in donut-shaped structures centered at active zones of neuromuscular synapses by using subdiffraction resolution STED (stimulated emission depletion) fluorescence microscopy. At brp mutant active zones, electron-dense projections (T-bars) were entirely lost, Ca2+ channels were reduced in density, evoked vesicle release was depressed, and short-term plasticity was altered. BRP-like proteins seem to establish proximity between Ca2+ channels and vesicles to allow efficient transmitter release and patterned synaptic plasticity.


Journal of Cell Biology | 2009

Maturation of active zone assembly by Drosophila Bruchpilot

Wernher Fouquet; David Owald; Carolin Wichmann; Sara Mertel; Harald Depner; Marcus Dyba; Stefan Hallermann; Robert J. Kittel; Stefan Eimer; Stephan J. Sigrist

Synaptic vesicles fuse at active zone (AZ) membranes where Ca2+ channels are clustered and that are typically decorated by electron-dense projections. Recently, mutants of the Drosophila melanogaster ERC/CAST family protein Bruchpilot (BRP) were shown to lack dense projections (T-bars) and to suffer from Ca2+ channel–clustering defects. In this study, we used high resolution light microscopy, electron microscopy, and intravital imaging to analyze the function of BRP in AZ assembly. Consistent with truncated BRP variants forming shortened T-bars, we identify BRP as a direct T-bar component at the AZ center with its N terminus closer to the AZ membrane than its C terminus. In contrast, Drosophila Liprin-α, another AZ-organizing protein, precedes BRP during the assembly of newly forming AZs by several hours and surrounds the AZ center in few discrete punctae. BRP seems responsible for effectively clustering Ca2+ channels beneath the T-bar density late in a protracted AZ formation process, potentially through a direct molecular interaction with intracellular Ca2+ channel domains.


Nature Neuroscience | 2005

Glutamate receptor dynamics organizing synapse formation in vivo

Tobias M. Rasse; Wernher Fouquet; Andreas Schmid; Robert J. Kittel; Sara Mertel; Carola B. Sigrist; Manuela Schmidt; Asja Guzman; Carlos Merino; Gang Qin; Christine Quentin; Frank Madeo; Manfred Heckmann; Stephan J. Sigrist

Insight into how glutamatergic synapses form in vivo is important for understanding developmental and experience-triggered changes of excitatory circuits. Here, we imaged postsynaptic densities (PSDs) expressing a functional, GFP-tagged glutamate receptor subunit (GluR-IIAGFP) at neuromuscular junctions of Drosophila melanogaster larvae for several days in vivo. New PSDs, associated with functional and structural presynaptic markers, formed independently of existing synapses and grew continuously until reaching a stable size within hours. Both in vivo photoactivation and photobleaching experiments showed that extrasynaptic receptors derived from diffuse, cell-wide pools preferentially entered growing PSDs. After entering PSDs, receptors were largely immobilized. In comparison, other postsynaptic proteins tested (PSD-95, NCAM and PAK homologs) exchanged faster and with no apparent preference for growing synapses. We show here that new glutamatergic synapses form de novo and not by partitioning processes from existing synapses, suggesting that the site-specific entry of particular glutamate receptor complexes directly controls the assembly of individual PSDs.


Brain | 2010

Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition

Christian Geis; Andreas Weishaupt; Stefan Hallermann; Benedikt Grünewald; Carsten Wessig; Thomas Wultsch; Andreas Reif; Nadiya Byts; Marcus Beck; Sibylle Jablonka; Michael Karl Boettger; Nurcan Üçeyler; Wernher Fouquet; Manfred Gerlach; Hans-Michael Meinck; Anna-Leena Sirén; Stephan J. Sigrist; Klaus V. Toyka; Manfred Heckmann; Claudia Sommer

Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.


Journal of Cell Biology | 2010

A Syd-1 homologue regulates pre- and postsynaptic maturation in Drosophila

David Owald; Wernher Fouquet; Manuela Schmidt; Carolin Wichmann; Sara Mertel; Harald Depner; Frauke Christiansen; Christina Zube; Christine Quentin; Jorg Körner; Henning Urlaub; Karl Mechtler; Stephan J. Sigrist

A proteomics approach identifies Drosophila Syd-1 as a Bruchpilot binding partner that controls maturation on both sides of the neuromuscular junction.


Neuron | 2010

Drosophila Neuroligin 1 Promotes Growth and Postsynaptic Differentiation at Glutamatergic Neuromuscular Junctions

Daniel Banovic; Omid Khorramshahi; David Owald; Carolin Wichmann; Tamara Riedt; Wernher Fouquet; Rui Tian; Stephan J. Sigrist; Hermann Aberle

Precise apposition of presynaptic and postsynaptic domains is a fundamental property of all neuronal circuits. Experiments in vitro suggest that Neuroligins and Neurexins function as key regulatory proteins in this process. In a genetic screen, we recovered several mutant alleles of Drosophila neuroligin 1 (dnlg1) that cause a severe reduction in bouton numbers at neuromuscular junctions (NMJs). In accord with reduced synapse numbers, these NMJs show reduced synaptic transmission. Moreover, lack of postsynaptic DNlg1 leads to deficits in the accumulation of postsynaptic glutamate receptors, scaffold proteins, and subsynaptic membranes, while increased DNlg1 triggers ectopic postsynaptic differentiation via its cytoplasmic domain. DNlg1 forms discrete clusters adjacent to postsynaptic densities. Formation of these clusters depends on presynaptic Drosophila Neurexin (DNrx). However, DNrx binding is not an absolute requirement for DNlg1 function. Instead, other signaling components are likely involved in DNlg1 transsynaptic functions, with essential interactions organized by the DNlg1 extracellular domain but also by the cytoplasmic domain.


Nature Neuroscience | 2012

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

David Owald; Omid Khorramshahi; Varun K Gupta; Daniel Banovic; Harald Depner; Wernher Fouquet; Carolin Wichmann; Sara Mertel; Stefan Eimer; Eric Reynolds; Matthew Holt; Hermann Aberle; Stephan J. Sigrist

Synapse formation and maturation requires bidirectional communication across the synaptic cleft. The trans-synaptic Neurexin-Neuroligin complex can bridge this cleft, and severe synapse assembly deficits are found in Drosophila melanogaster neuroligin (Nlg1, dnlg1) and neurexin (Nrx-1, dnrx) mutants. We show that the presynaptic active zone protein Syd-1 interacts with Nrx-1 to control synapse formation at the Drosophila neuromuscular junction. Mutants in Syd-1 (RhoGAP100F, dsyd-1), Nrx-1 and Nlg1 shared active zone cytomatrix defects, which were nonadditive. Syd-1 and Nrx-1 formed a complex in vivo, and Syd-1 was important for synaptic clustering and immobilization of Nrx-1. Consequently, postsynaptic clustering of Nlg1 was affected in Syd-1 mutants, and in vivo glutamate receptor incorporation was changed in Syd-1, Nrx-1 and Nlg1 mutants. Stabilization of nascent Syd-1–Liprin-α (DLiprin-α) clusters, important to initialize active zone formation, was Nlg1 dependent. Thus, cooperation between Syd-1 and Nrx-1–Nlg1 seems to orchestrate early assembly processes between pre- and postsynaptic membranes, promoting avidity of newly forming synaptic scaffolds.


The Journal of Neuroscience | 2010

Naked dense bodies provoke depression.

Stefan Hallermann; Robert J. Kittel; Carolin Wichmann; Annika Weyhersmüller; Wernher Fouquet; Sara Mertel; David Owald; Stefan Eimer; Harald Depner; Martin Schwärzel; Stephan J. Sigrist; Manfred Heckmann

At presynaptic active zones (AZs), the frequently observed tethering of synaptic vesicles to an electron-dense cytomatrix represents a process of largely unknown functional significance. Here, we identified a hypomorphic allele, brpnude, lacking merely the last 1% of the C-terminal amino acids (17 of 1740) of the active zone protein Bruchpilot. In brpnude, electron-dense bodies were properly shaped, though entirely bare of synaptic vesicles. While basal glutamate release was unchanged, paired-pulse and sustained stimulation provoked depression. Furthermore, rapid recovery following sustained release was slowed. Our results causally link, with intramolecular precision, the tethering of vesicles at the AZ cytomatrix to synaptic depression.


The Journal of Neuroscience | 2011

Presynapses in Kenyon Cell Dendrites in the Mushroom Body Calyx of Drosophila

Frauke Christiansen; Christina Zube; Till F.M. Andlauer; Carolin Wichmann; Wernher Fouquet; David Owald; Sara Mertel; Florian Leiss; Gaia Tavosanis; Abud J. Farca Luna; André Fiala; Stephan J. Sigrist

Plastic changes at the presynaptic sites of the mushroom body (MB) principal neurons called Kenyon cells (KCs) are considered to represent a neuronal substrate underlying olfactory learning and memory. It is generally believed that presynaptic and postsynaptic sites of KCs are spatially segregated. In the MB calyx, KCs receive olfactory input from projection neurons (PNs) on their dendrites. Their presynaptic sites, however, are thought to be restricted to the axonal projections within the MB lobes. Here, we show that KCs also form presynapses along their calycal dendrites, by using novel transgenic tools for visualizing presynaptic active zones and postsynaptic densities. At these presynapses, vesicle release following stimulation could be observed. They reside at a distance from the PN input into the KC dendrites, suggesting that regions of presynaptic and postsynaptic differentiation are segregated along individual KC dendrites. KC presynapses are present in γ-type KCs that support short- and long-term memory in adult flies and larvae. They can also be observed in α/β-type KCs, which are involved in memory retrieval, but not in α′/β′-type KCs, which are implicated in memory acquisition and consolidation. We hypothesize that, as in mammals, recurrent activity loops might operate for memory retrieval in the fly olfactory system. The newly identified KC-derived presynapses in the calyx are, inter alia, candidate sites for the formation of memory traces during olfactory learning.


Developmental Neurobiology | 2009

Characterization of dendritic spines in the Drosophila central nervous system

Florian Leiss; Ewa Koper; Irina Hein; Wernher Fouquet; Jana Lindner; Stephan J. Sigrist; Gaia Tavosanis

Dendritic spines are a characteristic feature of a number of neurons in the vertebrate nervous system and have been implicated in processes that include learning and memory. In spite of this, there has been no comprehensive analysis of the presence of spines in a classical genetic system, such as Drosophila, so far. Here, we demonstrate that a subset of processes along the dendrites of visual system interneurons in the adult fly central nervous system, called LPTCs, closely resemble vertebrate spines, based on a number of criteria. First, the morphology, size, and density of these processes are very similar to those of vertebrate spines. Second, they are enriched in actin and devoid of tubulin. Third, they are sites of synaptic connections based on confocal and electron microscopy. Importantly, they represent a preferential site of localization of an acetylcholine receptor subunit, suggesting that they are sites of excitatory synaptic input. Finally, their number is modulated by the level of the small GTPase dRac1. Our results provide a basis to dissect the genetics of dendritic spine formation and maintenance and the functional role of spines.

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Sara Mertel

Free University of Berlin

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Harald Depner

Free University of Berlin

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