Leibniz Institute of Neurobiology

Magdeburg, Germany

Leibniz Institute of Neurobiology

Magdeburg, Germany
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Czondor K.,Institut Universitaire de France | Mondin M.,Institut Universitaire de France | Mondin M.,The Interdisciplinary Center | Garcia M.,Institut Universitaire de France | And 9 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Trafficking of AMPA receptors (AMPARs) plays a key role in synaptic transmission. However, a general framework integrating the two major mechanisms regulating AMPAR delivery at postsynapses (i.e., surface diffusion and internal recycling) is lacking. To this aim, we built a model based on numerical trajectories of individual AMPARs, including free diffusion in the extrasynaptic space, confinement in the synapse, and trapping at the postsynaptic density (PSD) through reversible interactions with scaffold proteins. The AMPAR/scaffold kinetic rates were adjusted by comparing computer simulations to single-particle tracking and fluorescence recovery after photobleaching experiments in primary neurons, in different conditions of synapse density and maturation. The model predicts that the steady-state AMPAR number at synapses is bidirectionally controlled by AMPAR/scaffold binding affinity and PSD size. To reveal the impact of recycling processes in basal conditions and upon synaptic potentiation or depression, spatially and temporally defined exocytic and endocytic events were introduced. The model predicts that local recycling of AMPARs close to the PSD, coupled to short-range surface diffusion, provides rapid control of AMPAR number at synapses. In contrast, because of long-range diffusion limitations, extrasynaptic recycling is intrinsically slower and less synapse-specific. Thus, by discriminating the relative contributions of AMPAR diffusion, trapping, and recycling events on spatial and temporal bases, this model provides unique insights on the dynamic regulation of synaptic strength.

Hoefer M.,Otto Von Guericke University of Magdeburg | Tyll S.,Otto Von Guericke University of Magdeburg | Kanowski M.,Otto Von Guericke University of Magdeburg | Brosch M.,Leibniz Institute of Neurobiology | And 6 more authors.
NeuroImage | Year: 2013

Although multisensory integration has been an important area of recent research, most studies focused on audiovisual integration. Importantly, however, the combination of audition and touch can guide our behavior as effectively which we studied here using psychophysics and functional magnetic resonance imaging (fMRI). We tested whether task-irrelevant tactile stimuli would enhance auditory detection, and whether hemispheric asymmetries would modulate these audiotactile benefits using lateralized sounds. Spatially aligned task-irrelevant tactile stimuli could occur either synchronously or asynchronously with the sounds. Auditory detection was enhanced by non-informative synchronous and asynchronous tactile stimuli, if presented on the left side. Elevated fMRI-signals to left-sided synchronous bimodal stimulation were found in primary auditory cortex (A1). Adjacent regions (planum temporale, PT) expressed enhanced BOLD-responses for synchronous and asynchronous left-sided bimodal conditions. Additional connectivity analyses seeded in right-hemispheric A1 and PT for both bimodal conditions showed enhanced connectivity with right-hemispheric thalamic, somatosensory and multisensory areas that scaled with subjects' performance. Our results indicate that functional asymmetries interact with audiotactile interplay which can be observed for left-lateralized stimulation in the right hemisphere. There, audiotactile interplay recruits a functional network of unisensory cortices, and the strength of these functional network connections is directly related to subjects' perceptual sensitivity. © 2013 Elsevier Inc.

Durschmid S.,Helen Wills Neuroscience Institute | Durschmid S.,Leibniz Institute of Neurobiology | Zaehle T.,Leibniz Institute of Neurobiology | Zaehle T.,Otto Von Guericke University of Magdeburg | And 13 more authors.
Cerebral Cortex | Year: 2016

Rapid changes in the environment evoke a comparison between expectancy and actual outcome to inform optimal subsequent behavior. The nucleus accumbens (NAcc), a key interface between the hippocampus and neocortical regions, is a candidate region for mediating this comparison. Here, we report event-related potentials obtained from the NAcc using direct intracranial recordings in 5 human participants while they listened to trains of auditory stimuli differing in their degree of deviation from repetitive background stimuli. NAcc recordings revealed an early mismatch signal (50-220 ms) in response to all deviants. NAcc activity in this time window was also sensitive to the statistics of stimulus deviancy, with larger amplitudes as a function of the level of deviancy. Importantly, this NAcc mismatch signal also predicted generation of longer latency scalp potentials (300-400 ms). The results provide direct human evidence that the NAcc is a key component of a network engaged in encoding statistics of the sensory environmental. © 2014 The Author. Published by Oxford University Press. All rights reserved.

Born G.,University of Munster | Breuer D.,University of Munster | Wang S.,University of Munster | Rohlmann A.,University of Munster | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like a-neurexins (a-Nrxn) and their extracellular binding partners determine synapse function. Although a-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an a-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABAB receptor (GABABR)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABABR, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABABR. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABABR with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABAAR with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABABR and postsynaptic GABAAR. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA AR and GABABR subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors.

Wagenbreth C.,Otto Von Guericke University of Magdeburg | Wattenberg L.,Otto Von Guericke University of Magdeburg | Heinze H.-J.,Otto Von Guericke University of Magdeburg | Heinze H.-J.,Leibniz Institute of Neurobiology | Zaehle T.,Otto Von Guericke University of Magdeburg
Behavioural Brain Research | Year: 2016

Objective: Besides motor problems, Parkinson's disease (PD) is associated with detrimental emotional and cognitive functioning. Deficient explicit emotional processing has been observed, whilst patients also show impaired Theory of Mind (ToM) abilities. However, it is unclear whether this PD patients' ToM deficit is based on an inability to infer otherś emotional states or whether it is due to explicit emotional processing deficits. We investigated implicit and explicit emotional processing in PD with an affective priming paradigm in which we used pictures of human eyes for emotional primes and a lexical decision task (LDT) with emotional connoted words for target stimuli. Method: Sixteen PD patients and sixteen matched healthy controls performed a LTD combined with an emotional priming paradigm providing emotional information through the facial eye region to assess implicit emotional processing. Second, participants explicitly evaluated the emotional status of eyes and words used in the implicit task. Results: Compared to controls implicit emotional processing abilities were generally preserved in PD with, however, considerable alterations for happiness and disgust processing. Furthermore, we observed a general impairment of patients for explicit evaluation of emotional stimuli, which was augmented for the rating of facial expressions. Conclusions: This is the first study reporting results for affective priming with facial eye expressions in PD patients. Our findings indicate largely preserved implicit emotional processing, with a specific altered processing of disgust and happiness. Explicit emotional processing was considerably impaired for semantic and especially for facial stimulus material. Poor ToM abilities in PD patients might be based on deficient explicit emotional processing, with preserved ability to implicitly infer other people's feelings. © 2016 Elsevier B.V.

Bose T.,Leibniz Institute of Neurobiology | Cieslar-Pobuda A.,Linköping University | Cieslar-Pobuda A.,Silesian University of Technology | Wiechec E.,Linköping University
Cell Death and Disease | Year: 2015

Ion channels are abundantly expressed in both excitable and non-excitable cells, thereby regulating the Ca2+ influx and downstream signaling pathways of physiological processes. The immune system is specialized in the process of cancer cell recognition and elimination, and is regulated by different ion channels. In comparison with the immune cells, ion channels behave differently in cancer cells by making the tumor cells more hyperpolarized and influence cancer cell proliferation and metastasis. Therefore, ion channels comprise an important therapeutic target in anti-cancer treatment. In this review, we discuss the implication of ion channels in regulation of Ca2+ homeostasis during the crosstalk between immune and cancer cell as well as their role in cancer progression. © 2015 Macmillan Publishers Limited. All rights reserved.

Malatynska E.,Lilly Research Labs Lilly Corporate Center | Steinbusch H.W.M.,Maastricht University | Redkozubova O.,Russian Academy of Sciences | Bolkunov A.,Russian Academy of Sciences | And 5 more authors.
Experimental Gerontology | Year: 2012

The prevalence of depression increases with aging. We hypothesized that like humans, old animals exhibit anhedonic-like behavior, along with signs of behavioral despair. In rodents, anhedonia, a reduced sensitivity to reward, which is listed as a core feature of major depression in the DSM-IVR, can be measured by a decrease in intake of and preference for sweet solutions. Here, sucrose intake, forced swimming, immobility in the modified tail suspension test, novelty exploration, grooming, anxiety and locomotor activity were compared in naïve 3- and 18-month-old male C57BL/6 mice. The absolute amounts and the ratio of consumed 1% sucrose solution to water intake was significantly smaller in 18-month-old mice than in 3-month-old mice. The consumption of 5%-sucrose solution requiring high levels of drinking effort, novelty exploration in two setups and grooming behavior in the splash test were reduced in older animals. Analysis of other behaviors suggested that the above-mentioned signs of anhedonic-like traits were unlikely to be attributable to the potential effect of aging on metabolic needs for water, taste perception, motor capabilities or the induction of essential anxiety and neophobia. A 4-week treatment with the antidepressant imipramine (7. mg/kg/day) or dimebon, a compound with suggested neuroprotective proneurogenic properties (1. mg/kg/day) restored sucrose intake and preference in 18-month-old mice. Meanwhile, young and old mice showed no differences in the parameters of behavioral despair evaluated in the forced swim and modified tail suspension tests. Thus, the behavioral profile of aged mice parallels that of humans with elderly depression, in whom the symptoms of hedonic deficits typically outweigh affective disturbances. The assessment of anhedonic-like traits with the sucrose preference test in 18-month-old mice will be useful in preclinical studies of elderly depression. © 2012 Elsevier Inc.

Biermann B.,Leibniz Institute of Neurobiology | Biermann B.,University of Munster | Sokoll S.,Leibniz Institute of Neurobiology | Klueva J.,Leibniz Institute of Neurobiology | And 5 more authors.
Nature Communications | Year: 2014

Organization of signalling molecules in biological membranes is crucial for cellular communication. Many receptors, ion channels and cell adhesion molecules are associated with proteins important for their trafficking, surface localization or function. These complexes are embedded in a lipid environment of varying composition. Binding affinities and stoichiometry of such complexes were so far experimentally accessible only in isolated systems or monolayers of cell culture. Visualization of molecular dynamics within signalling complexes and their correlation to specialized membrane compartments demand high temporal and spatial resolution and has been difficult to demonstrate in complex tissue like brain slices. Here we demonstrate the feasibility of single-particle tracking (SPT) in organotypic brain slices to measure molecular dynamics of lipids and transmembrane proteins in correlation to synaptic membrane compartments. This method will provide important information about the dynamics and organization of surface molecules in the complex environment of neuronal networks within brain slices. © 2014 Macmillan Publishers Limited. All rights reserved.

Neupert C.,University of Munster | Schneider R.,Leibniz Institute of Neurobiology | Klatt O.,University of Munster | Klatt O.,Leibniz Institute of Neurobiology | And 8 more authors.
Journal of Neuroscience | Year: 2015

Synapses depend on trafficking of key membrane proteins by lateral diffusion from surface populations and by exocytosis from intracellular pools. The cell adhesion molecule neurexin (Nrxn) plays essential roles in synapses, but the dynamics and regulation of its trafficking are unknown. Here, we performed single-particle tracking and live imaging of transfected, epitope-tagged Nrxn variants in cultured rat and mouse wild-type or knock-out neurons. We observed that structurally larger αNrxn molecules are more mobile in the plasma membrane than smaller βNrxns because αNrxns displayed higher diffusion coefficients in extrasynaptic regions and excitatory or inhibitory terminals. We found that well characterized interactions with extracellular binding partners regulate the surface mobility of Nrxns. Binding to neurexophilin-1 (Nxph1) reduced the surface diffusion of αNrxns when both molecules were coexpressed. Conversely, impeding other interactions by insertion of splice sequence #4 or removal of extracellular Ca2+ augmented the mobility of αNrxns and βNrxns. We also determined that fast axonal transport delivers Nrxns to the neuronal surface because Nrxns comigrate as cargo on synaptic vesicle protein transport vesicles (STVs). Unlike surface mobility, intracellular transport of βNrxn+ STVs was faster than that of αNrxns, but both depended on the microtubule motor protein KIF1A and neuronal activity regulated the velocity. Large spontaneous fusion of Nrxn+ STVs occurred simultaneously with synaptophysin on axonal membranes mostly outside of active presynaptic terminals. Surface Nrxns enriched at synaptic terminals where αNrxns and Nxph1/αNrxns recruited GABAAR subunits. Therefore, our results identify regulated dynamic trafficking as an important property of Nrxns that corroborates their function at synapses. © 2015, the authors.

PubMed | Otto Von Guericke University of Magdeburg, Leibniz Institute of Neurobiology, Innsbruck Medical University and University of Munster
Type: Journal Article | Journal: Neurophotonics | Year: 2016

High voltage gated calcium channels (VGCCs) are composed of at least three subunits, one pore forming [Formula: see text]-subunit, an intracellular [Formula: see text]-variant, and a mostly extracellular [Formula: see text]-variant. Interactions between these subunits determine the kinetic properties of VGCCs. It is unclear whether these interactions are stable over time or rather transient. Here, we used single-molecule tracking to investigate the surface diffusion of [Formula: see text]- and [Formula: see text]-subunits at the cell surface. We found that [Formula: see text]-subunits show higher surface mobility than [Formula: see text]-subunits, and that they are only transiently confined together, suggesting a weak association between [Formula: see text]- and [Formula: see text]-subunits. Moreover, we observed that different [Formula: see text]-subunits engage in different degrees of association with the [Formula: see text]-subunit, revealing the tighter interaction of [Formula: see text] with [Formula: see text]. These data indicate a distinct regulation of the [Formula: see text] interaction in VGCC subtypes. We modeled their membrane dynamics in a Monte Carlo simulation using experimentally determined diffusion constants. Our modeling predicts that the ratio of associated [Formula: see text]- and [Formula: see text]-subunits mainly depends on their expression density and confinement in the membrane. Based on the different motilities of particular [Formula: see text]-subunit combinations, we propose that their dynamic assembly and disassembly represent an important mechanism to regulate the signaling properties of VGCC.

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