European Neuroscience Institute Gottingen

Göttingen, Germany

European Neuroscience Institute Gottingen

Göttingen, Germany
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Delvendahl I.,European Neuroscience Institute Gottingen | Lindemann H.,Albert Ludwigs University of Freiburg | Heidegger T.,Goethe University Frankfurt | Normann C.,Albert Ludwigs University of Freiburg | And 2 more authors.
Clinical Neurophysiology | Year: 2013

Objective: Besides its use in epilepsy, lamotrigine (LTG) is also effective as mood stabilizer. The pathophysiology of mood disorders may incorporate a dysfunction of neuronal plasticity and animal experiments suggest that mood stabilizers influence induction of long-term potentiation (LTP) and -depression (LTD), two major forms of synaptic plasticity. However, the exact modes of action of LTG and its impact on neuronal plasticity in humans remain unclear. Methods: Here, we tested the effects of a single oral dose of LTG (300mg) on motor cortical plasticity induced by paired associative stimulation (PAS25), a protocol that typically induces LTP-like plasticity, in 26 young healthy adults in a placebo-controlled, randomized, double-blind crossover design. We stratified analysis of the LTG effects according to the individual PAS25 response in the placebo session (14 LTP-responders vs. 12 LTD-responders). Plasticity was indexed by motor evoked potential (MEP) amplitudes recorded before and for 60min after PAS25. Results: LTG resulted in a significant reduction of the LTP-like MEP increase in the LTP-responders and a reduction of the LTD-like MEP decrease in the LTD-responders, with the majority of LTD-responders even showing an MEP increase. Conclusions: In summary, LTG differentially modulated cortical plasticity induced by non-invasive brain stimulation in human subjects depending on their individual intrinsic propensity for expressing LTP-like or LTD-like plasticity. Significance: Findings contribute to our understanding of the anticonvulsant and antidepressant clinical effects of LTG, which have been suggested to occur, at least in part, through downregulation of LTP (epilepsy) and LTD (depressive disorders). © 2012 International Federation of Clinical Neurophysiology.


Ritzau-Jost A.,University of Leipzig | Ritzau-Jost A.,European Neuroscience Institute Gottingen | Delvendahl I.,University of Leipzig | Delvendahl I.,European Neuroscience Institute Gottingen | And 11 more authors.
Neuron | Year: 2014

Fast synaptic transmission is important for rapid information processing. To explore the maximal rate of neuronal signaling and to analyze the presynaptic mechanisms, we focused on the input layer of the cerebellar cortex, where exceptionally high action potential (AP) frequencies have been reported invivo. With paired recordings between presynaptic cerebellar mossy fiber boutons and postsynaptic granule cells, we demonstrate reliable neurotransmission upto ~1 kHz. Presynaptic APs are ultrafast, with ~100μs half-duration. Both Kv1 and Kv3 potassium channels mediate the fast repolarization, rapidly inactivating sodium channels ensure metabolic efficiency, and little AP broadening occurs during bursts of up to 1.5 kHz. Presynaptic Cav2.1 (P/Q-type) calcium channels open efficiently during ultrafast APs. Furthermore, a subset of synaptic vesicles is tightly coupled to Ca2+ channels, and vesicles are rapidly recruited to the release site. These data reveal mechanisms of presynaptic AP generation and transmitter release underlying neuronal kHz signaling. © 2014 Elsevier Inc.


Delvendahl I.,University of Leipzig | Delvendahl I.,European Neuroscience Institute Gottingen | Lindemann H.,Albert Ludwigs University of Freiburg | Jung N.H.,TU Munich | And 3 more authors.
Brain Stimulation | Year: 2014

Transcranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF). Objective/hypothesis We examined whether SICF depends on waveform and current direction of the TMS pulses. Methods In young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior-anterior (PA) or anterior-posterior (AP) current direction (AP-AP or PA-PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA-AP and AP-PA). Results Monophasic AP-AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA-PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA-AP current orientation compared with AP-PA. Conclusion SICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF. © 2014 Elsevier Inc. All rights reserved.


Rassow J.,Ruhr University Bochum | Meinecke M.,University of Gottingen | Meinecke M.,European Neuroscience Institute Gottingen
Microbes and Infection | Year: 2012

The vacuolating cytotoxin VacA, a polypeptide of about 88 kDa, is one of the major virulence factors of Helicobacter pylori. VacA essentially acts as an invasive chloride channel targeting mitochondria. The results of recent studies open a new perspective on the mechanisms by which VacA causes loss of the mitochondrial membrane potential, mitochondrial fragmentation, formation of reactive oxygen species, autophagy, cell death and gastric cancer. © 2012 Institut Pasteur.


Welzel O.,Friedrich - Alexander - University, Erlangen - Nuremberg | Henkel A.W.,Kuwait University | Stroebel A.M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Jung J.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 5 more authors.
Biophysical Journal | Year: 2011

Hippocampal neurons in tissue culture develop functional synapses that exhibit considerable variation in synaptic vesicle content (20-350 vesicles). We examined absolute and fractional parameters of synaptic vesicle exocytosis of individual synapses. Their correlation to vesicle content was determined by activity-dependent discharge of FM-styryl dyes. At high frequency stimulation (30 Hz), synapses with large recycling pools released higher amounts of dye, but showed a lower fractional release compared to synapses that contained fewer vesicles. This effect gradually vanished at lower frequencies when stimulation was triggered at 20 Hz and 10 Hz, respectively. Live-cell antibody staining with anti-synaptotagmin-1-cypHer 5, and overexpression of synaptopHluorin as well as photoconversion of FM 1-43 followed by electron microscopy, consolidated the findings obtained with FM-styryl dyes. We found that the readily releasable pool grew with a power function with a coefficient of 2/3, possibly indicating a synaptic volume/surface dependency. This observation could be explained by assigning the ratelimiting factor for vesicle exocytosis at high frequency stimulation to the available active zone surface that is proportionally smaller in synapses with larger volumes. © 2011 by the Biophysical Society.


Barbot M.,University of Gottingen | Jans D.C.,Max Planck Institute for Biophysical Chemistry | Jans D.C.,University of Gottingen | Schulz C.,University of Gottingen | And 7 more authors.
Cell Metabolism | Year: 2015

The mitochondrial inner membrane is highly folded and displays a complex molecular architecture. Cristae junctions are highly curved tubular openings that separate cristae membrane invaginations from the surrounding boundary membrane. Despite their central role in many vital cellular processes like apoptosis, the details of cristae junction formation remain elusive. Here we identify Mic10, a core subunit of the recently discovered MICOS complex, as an inner mitochondrial membrane protein with the ability to change membrane morphology in vitro and in vivo. We show that Mic10 spans the inner membrane in a hairpin topology and that its ability to sculpt membranes depends on oligomerization through a glycine-rich motif. Oligomerization mutants fail to induce curvature in model membranes, and when expressed in yeast, mitochondria display an altered inner membrane architecture characterized by drastically decreased numbers of cristae junctions. Thus, we demonstrate that membrane sculpting by Mic10 is essential for cristae junction formation. © 2015 Elsevier Inc.


Bonanomi D.,Salk Institute for Biological Studies | Chivatakarn O.,Salk Institute for Biological Studies | Bai G.,Salk Institute for Biological Studies | Abdesselem H.,University of Michigan | And 4 more authors.
Cell | Year: 2012

Growing axons encounter multiple guidance cues, but it is unclear how separate signals are resolved and integrated into coherent instructions for growth cone navigation. We report that glycosylphosphatidylinositol (GPI)-anchored ephrin-As function as "reverse" signaling receptors for motor axons when contacted by transmembrane EphAs present in the dorsal limb. Ephrin-A receptors are thought to depend on transmembrane coreceptors for transmitting signals intracellularly. We show that the receptor tyrosine kinase Ret is required for motor axon attraction mediated by ephrin-A reverse signaling. Ret also mediates GPI-anchored GFRα1 signaling in response to GDNF, a diffusible chemoattractant in the limb, indicating that Ret is a multifunctional coreceptor for guidance molecules. Axons respond synergistically to coactivation by GDNF and EphA ligands, and these cooperative interactions are gated by GFRα1 levels. Our studies uncover a hierarchical GPI-receptor signaling network that is constructed from combinatorial components and integrated through Ret using ligand coincidence detection. © 2012 Elsevier Inc.


Schmidt H.,University of Leipzig | Brachtendorf S.,University of Leipzig | Arendt O.,University of Leipzig | Hallermann S.,University of Leipzig | And 7 more authors.
Current Biology | Year: 2013

The coupling distance between presynaptic Ca2+ influx and the sensor for vesicular transmitter release determines speed and reliability of synaptic transmission [1, 2]. Nanodomain coupling (<100 nm) favors fidelity [1, 2] and is employed by synapses specialized for escape reflexes [3] and by inhibitory synapses involved in synchronizing fast network oscillations [1]. Cortical glutamatergic synapses seem to forgo the benefits of tight coupling [4-6], yet quantitative detail is lacking [2, 7]. The reduced transmission fidelity of loose coupling, however, raises the question whether it is indeed a general characteristic of cortical synapses. Here we analyzed excitatory parallel fiber to Purkinje cell synapses, major processing sites for sensory information [8] and well suited for analysis because they typically harbor only a single active zone [9]. We quantified the coupling distance by combining multiprobability fluctuation analyses, presynaptic Ca2+ imaging, and reaction-diffusion simulations in wild-type and calretinin-deficient mice. We found a coupling distance of <30 nm at these synapses, much shorter than at any other glutamatergic cortical synapse investigated to date. Our results suggest that nanodomain coupling is a general characteristic of conventional cortical synapses involved in high-frequency transmission, allowing for dense gray matter packing and cost-effective neurotransmission. © 2013 Elsevier Ltd.


Opazo F.,European Neuroscience Institute Gottingen | Rizzoli S.O.,European Neuroscience Institute Gottingen
Journal of Visualized Experiments | Year: 2010

The fusion of synaptic vesicles with the plasma membrane (exocytosis) is a required step in neurotransmitter release and neuronal communication. The vesicles are then retrieved from the plasma membrane (endocytosis) and grouped together with the general pool of vesicles within the nerve terminal, until they undergo a new exo- and endocytosis cycle (vesicle recycling). These processes have been studied using a variety of techniques such as electron microscopy, electrophysiology recordings, amperometry and capacitance measurements. Importantly, during the last two decades a number of fluorescently labeled markers emerged, allowing optical techniques to track vesicles in their recycling dynamics. One of the most commonly used markers is the styryl or FM dye 1; structurally, all FM dyes contain a hydrophilic head and a lipophilic tail connected through an aromatic ring and one or more double bonds (Fig. 1B). A classical FM dye experiment to label a pool of vesicles consists in bathing the preparation (Fig. 1Ai) with the dye during the stimulation of the nerve (electrically or with high K +). This induces vesicle recycling and the subsequent loading of the dye into recently endocytosed vesicles (Fig. 1A I-III). After loading the vesicles with dye, a second round of stimulation in a dye-free bath would trigger the FM release through exocytosis (Fig. 1A IV-V), process that can be followed by monitoring the fluorescence intensity decrease (destaining). © JoVE 2006-2011 All Rights Reserved.


Bornschein G.,University of Leipzig | Arendt O.,University of Leipzig | Hallermann S.,European Neuroscience Institute Gottingen | Brachtendorf S.,University of Leipzig | And 2 more authors.
Journal of Physiology | Year: 2013

Paired-pulse facilitation (PPF) is a dynamic enhancement of transmitter release considered crucial in CNS information processing. The mechanisms of PPF remain controversial and may differ between synapses. Endogenous Ca2+ buffers such as parvalbumin (PV) and calbindin-D28k (CB) are regarded as important modulators of PPF, with PV acting as an anti-facilitating buffer while saturation of CB can promote PPF. We analysed transmitter release and PPF at intracortical, recurrent Purkinje neuron (PN) to PN synapses, which show PPF during high-frequency activation (200 Hz) and strongly express both PV and CB. We quantified presynaptic Ca2+ dynamics and quantal release parameters in wild-type (WT), and CB and PV deficient mice. Lack of CB resulted in increased volume averaged presynaptic Ca2+ amplitudes and in increased release probability, while loss of PV had no significant effect on these parameters. Unexpectedly, none of the buffers significantly influenced PPF, indicating that neither CB saturation nor residual free Ca2+ ([Ca2+]res) was the main determinant of PPF. Experimentally constrained, numerical simulations of Ca2+-dependent release were used to estimate the contributions of [Ca2+]res, CB, PV, calmodulin (CaM), immobile buffer fractions and Ca2+ remaining bound to the release sensor after the first of two action potentials ('active Ca2+') to PPF. This analysis indicates that PPF at PN-PN synapses does not result from either buffer saturation or [Ca2+]res but rather from slow Ca2+ unbinding from the release sensor. © 2013 The Authors. The Journal of Physiology © 2013 The Physiological Society.

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