European Neuroscience Institute Gottingen

Göttingen, Germany

European Neuroscience Institute Gottingen

Göttingen, Germany
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Hallermann S.,European Neuroscience Institute Gottingen | Hallermann S.,University of Leipzig | De Kock C.P.J.,VU University Amsterdam | Stuart G.J.,Australian National University | And 2 more authors.
Nature Neuroscience | Year: 2012

Action potential generation and conduction requires large quantities of energy to restore Na + and K + ion gradients. We investigated the subcellular location and voltage dependence of this metabolic cost in rat neocortical pyramidal neurons. Using Na +K + charge overlap as a measure of action potential energy efficiency, we found that action potential initiation in the axon initial segment (AIS) and forward propagation into the axon were energetically inefficient, depending on the resting membrane potential. In contrast, action potential backpropagation into dendrites was efficient. Computer simulations predicted that, although the AIS and nodes of Ranvier had the highest metabolic cost per membrane area, action potential backpropagation into the dendrites and forward propagation into axon collaterals dominated energy consumption in cortical pyramidal neurons. Finally, we found that the high metabolic cost of action potential initiation and propagation down the axon is a trade-off between energy minimization and maximization of the conduction reliability of high-frequency action potentials. © 2012 Nature America, Inc. All rights reserved.

Hallermann S.,European Neuroscience Institute Gottingen | Silver R.A.,University College London
Trends in Neurosciences | Year: 2013

Rapid information processing in our nervous system relies on high-frequency fusion of transmitter-filled vesicles at chemical synapses. Some sensory synapses possess prominent electron-dense ribbon structures that provide a scaffold for tethering synaptic vesicles at the active zone (AZ), enabling sustained vesicular release. Here, we review functional data indicating that some central and neuromuscular synapses can also sustain vesicle-fusion rates that are comparable to those of ribbon-type sensory synapses. Comparison of the ultrastructure across these different types of synapses, together with recent work showing that cytomatrix proteins can tether vesicles and speed vesicle reloading, suggests that filamentous structures may play a key role in vesicle supply. We discuss potential mechanisms by which vesicle tethering could contribute to sustained high rates of vesicle fusion across ribbon-type, central, and neuromuscular synapses. © 2012 Elsevier Ltd.

Banovic D.,University of Munster | Khorramshahi O.,Free University of Berlin | Owald D.,Free University of Berlin | Owald D.,Charité - Medical University of Berlin | And 7 more authors.
Neuron | Year: 2010

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. © 2010 Elsevier Inc.

Krishnamoorthy V.,University of Gottingen | Cherukuri P.,European Neuroscience Institute Gottingen | Poria D.,National Brain Research Center | Goel M.,National Brain Research Center | And 2 more authors.
Frontiers in Cellular Neuroscience | Year: 2016

Deafferentation results not only in sensory loss, but also in a variety of alterations in the postsynaptic circuitry. These alterations may have detrimental impact on potential treatment strategies. Progressive loss of photoreceptors in retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration, leads to several changes in the remnant retinal circuitry. Müller glial cells undergo hypertrophy and form a glial seal. The second- and third-order retinal neurons undergo morphological, biochemical and physiological alterations. A result of these alterations is that retinal ganglion cells (RGCs), the output neurons of the retina, become hyperactive and exhibit spontaneous, oscillatory bursts of spikes. This aberrant electrical activity degrades the signal-to-noise ratio in RGC responses, and thus the quality of information they transmit to the brain. These changes in the remnant retina, collectively termed “retinal remodeling”, pose challenges for genetic, cellular and bionic approaches to restore vision. It is therefore crucial to understand the nature of retinal remodeling, how it affects the ability of remnant retina to respond to novel therapeutic strategies, and how to ameliorate its effects. In this article, we discuss these topics, and suggest that the pathological state of the retinal output following photoreceptor loss is reversible, and therefore, amenable to restorative strategies. © 2016 Krishnamoorthy, Cherukuri, Poria, Goel, Dagar and Dhingra.

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.

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.

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.

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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