@article{BahnikStuchlik2015, author = {Bahn{\´i}k, Štěp{\´a}n and Stuchl{\´i}k, Aleš}, title = {Temporal and spatial strategies in an active place avoidance task on Carousel: a study of effects of stability of arena rotation speed in rats}, series = {PeerJ}, volume = {3}, journal = {PeerJ}, number = {e1257}, doi = {10.7717/peerj.1257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141931}, year = {2015}, abstract = {The active place avoidance task is a dry-arena task used to assess spatial navigation and memory in rodents. In this task, a subject is put on a rotating circular arena and avoids an invisible sector that is stable in relation to the room. Rotation of the arena means that the subject's avoidancemust be active, otherwise the subject will be moved in the to-be-avoided sector by the rotation of the arena and a slight electric shock will be administered. The present experiment explored the effect of variable arena rotation speed on the ability to avoid the to-be-avoided sector. Subjects in a group with variable arena rotation speed learned to avoid the sector with the same speed and attained the same avoidance ability as rats in a group with a stable arena rotation speed. Only a slight difference in preferred position within the room was found between the two groups. No difference was found between the two groups in the dark phase, where subjects could not use orientation cues in the room. Only one rat was able to learn the avoidance of the to-be-avoided sector in this phase. The results of the experiment suggest that idiothetic orientation and interval timing are not crucial for learning avoidance of the to-be-avoided sector. However, idiothetic orientation might be sufficient for avoiding the sector in the dark.}, language = {en} } @article{PaulPauliEhmannetal.2015, author = {Paul, Mila M. and Pauli, Martin and Ehmann, Nadine and Hallermann, Stefan and Sauer, Markus and Kittel, Robert J. and Heckmann, Manfred}, title = {Bruchpilot and Synaptotagmin collaborate to drive rapid glutamate release and active zone differentiation}, series = {Frontiers in Cellular Neuroscience}, volume = {9}, journal = {Frontiers in Cellular Neuroscience}, number = {29}, doi = {10.3389/fncel.2015.00029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148988}, year = {2015}, abstract = {The active zone (AZ) protein Bruchpilot (Brp) is essential for rapid glutamate release at Drosophila melanogaster neuromuscular junctions (NMJs). Quantal time course and measurements of action potential-waveform suggest that presynaptic fusion mechanisms are altered in brp null mutants (brp\(^{69}\)). This could account for their increased evoked excitatory postsynaptic current (EPSC) delay and rise time (by about 1 ms). To test the mechanism of release protraction at brp\(^{69}\) AZs, we performed knock-down of Synaptotagmin-1 (Syt) via RNAi (syt\(^{KD}\)) in wildtype (wt), brp\(^{69}\) and rab3 null mutants (rab3\(^{rup}\)), where Brp is concentrated at a small number of AZs. At wt and rab3\(^{rup}\) synapses, syt\(^{KD}\) lowered EPSC amplitude while increasing rise time and delay, consistent with the role of Syt as a release sensor. In contrast, syt\(^{KD}\) did not alter EPSC amplitude at brp\(^{69}\) synapses, but shortened delay and rise time. In fact, following syt\(^{KD}\), these kinetic properties were strikingly similar in wt and brp\(^{69}\), which supports the notion that Syt protracts release at brp\(^{69}\) synapses. To gain insight into this surprising role of Syt at brp\(^{69}\) AZs, we analyzed the structural and functional differentiation of synaptic boutons at the NMJ. At tonic type Ib motor neurons, distal boutons contain more AZs, more Brp proteins per AZ and show elevated and accelerated glutamate release compared to proximal boutons. The functional differentiation between proximal and distal boutons is Brp-dependent and reduced after syt\(^{KD}\). Notably, syt\(^{KD}\) boutons are smaller, contain fewer Brp positive AZs and these are of similar number in proximal and distal boutons. In addition, super-resolution imaging via dSTORM revealed that syt\(^{KD}\) increases the number and alters the spatial distribution of Brp molecules at AZs, while the gradient of Brp proteins per AZ is diminished. In summary, these data demonstrate that normal structural and functional differentiation of Drosophila AZs requires concerted action of Brp and Syt.}, language = {en} } @article{KollertDombertDoeringetal.2015, author = {Kollert, Sina and Dombert, Benjamin and D{\"o}ring, Frank and Wischmeyer, Erhard}, title = {Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {12548}, doi = {10.1038/srep12548}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148312}, year = {2015}, abstract = {In dorsal root ganglia (DRG) neurons TRESK channels constitute a major current component of the standing outward current IK\(_{SO}\). A prominent physiological role of TRESK has been attributed to pain sensation. During inflammation mediators of pain e.g. lysophosphatidic acid (LPA) are released and modulate nociception. We demonstrate co-expression of TRESK and LPA receptors in DRG neurons. Heterologous expression of TRESK and LPA receptors in Xenopus oocytes revealed augmentation of basal K\(^{+}\) currents upon LPA application. In DRG neurons nociception can result from TRPV\(_{1}\) activation by capsaicin or LPA. Upon co-expression in Xenopus oocytes LPA simultaneously increased both depolarising TRPV\(_{1}\) and hyperpolarising TRESK currents. Patch-clamp recordings in cultured DRG neurons from TRESK[wt] mice displayed increased IK\(_{SO}\) after application of LPA whereas under these conditions IK\(_{SO}\) in neurons from TRESK[ko] mice remained unaltered. Under current-clamp conditions LPA application differentially modulated excitability in these genotypes upon depolarising pulses. Spike frequency was attenuated in TRESK[wt] neurons and, in contrast, augmented in TRESK[ko] neurons. Accordingly, excitation of nociceptive neurons by LPA is balanced by co-activation of TRESK channels. Hence excitation of sensory neurons is strongly controlled by the activity of TRESK channels, which therefore are good candidates for the treatment of pain disorders.}, language = {en} } @article{BeckEhmannAndlaueretal.2015, author = {Beck, Katherina and Ehmann, Nadine and Andlauer, Till F. M. and Ljaschenko, Dmitrij and Strecker, Katrin and Fischer, Matthias and Kittel, Robert J. and Raabe, Thomas}, title = {Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons}, series = {Disease Models \& Mechanisms}, volume = {8}, journal = {Disease Models \& Mechanisms}, doi = {10.1242/dmm.021246}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145185}, pages = {1389-1400}, year = {2015}, abstract = {Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling.}, language = {en} } @phdthesis{Lausenmeyer2015, author = {Lausenmeyer, Eva Maria}, title = {Einfluss von Fractalkin und mfg-e8 auf die Thrombozytenaktivierung und ihre Interaktion mit pharmakologischen Thrombozytenaggregationshemmern}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134469}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Die genauen Mechanismen der fr{\"u}hen Atheroskleroseentstehung sind Thema intensiver Forschungsarbeit. Hierbei hat sich in den letzten Jahren eine zunehmend wichtige Rolle f{\"u}r Thrombozyten herauskristallisiert. Sie spielen nicht nur in der H{\"a}mostase, sondern auch bei immunologischen und entz{\"u}ndlichen Erkrankungen eine wichtige Rolle. Aktivierte Blutpl{\"a}ttchen interagieren auf vielf{\"a}ltige Weise mit unterschiedlichen Zellen ihrer Umgebung - Endothelzellen, glatten Muskelzellen oder Leukozyten - wodurch es auf beiden Seiten zur Freisetzung von Botenstoffen und nachfolgend zur Aktivierung diverser Signalwege kommt. Auf der Thrombozytenoberfl{\"a}che finden sich u.a. Rezeptoren f{\"u}r das Chemokin Fractalkin (CX3CL1). Dieses wurde bereits mit Thrombozytenaktivierung und Leukozytenadh{\"a}sion am Endothel in Verbindung gebracht. In dieser Arbeit konnte erstmals gezeigt werden, dass der thrombozyt{\"a}re ADP-Rezeptor P2Y12 und der Rezeptor f{\"u}r Fractalkin, CX3CR1, eine {\"a}hnliche intrazellul{\"a}re G-Protein-Kopplung und Signalkaskade aufweisen, die in der Aktivierung der PI3K m{\"u}ndet. Der Effekt ist unabh{\"a}ngig von einer ADP-Zugabe und wird {\"u}ber G vermittelt, so dass hier{\"u}ber eine Blockung des P2Y12-Rezeptors durch z.B. Clopidogrel umgangen werden k{\"o}nnte. Des Weiteren ist bekannt, dass Fractalkin die Expression des Glykoproteins mfg-e8 beeinflusst. Inwiefern mfg-e8 einen Einfluss auf Thrombozyten hat, ist bislang nur unzureichend erforscht. In der vorliegenden Arbeit konnte eine proaktivierende Wirkung von mfg-e8 auf Thrombozyten nachgewiesen werden: Sowohl im Western blot (Aktivierung der PI3K) wie auch durchflusszytometrisch (Aktivierung des GPIIb/IIIa). Unter arteriellen Flussbedingungen schw{\"a}chte mfg-e8 die Bindung von Thrombozyten an Fibrinogen-beschichtete Oberfl{\"a}chen ab. Welche Rezeptoren an dieser Interaktion beteiligt sind, ist derzeit nicht gekl{\"a}rt. Sowohl mfg-e8 als auch Fractalkin stellen interessante, thrombozytenaktivierenden Substanzen dar, deren Einfluss aufeinander und auf das Gef{\"a}ßsystem weiterf{\"u}hrender Untersuchung bedarf.}, subject = {Thrombozytenaggregationshemmung}, language = {de} } @article{ScholzGehringGuanetal.2015, author = {Scholz, Nicole and Gehring, Jennifer and Guan, Chonglin and Ljaschenko, Dmitrij and Fischer, Robin and Lakshmanan, Vetrivel and Kittel, Robert J. and Langenhan, Tobias}, title = {The adhesion GPCR Latrophilin/CIRL shapes mechanosensation}, series = {Cell Reports}, volume = {11}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2015.04.008}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148626}, pages = {866-874}, year = {2015}, abstract = {G-protein-coupled receptors (GPCRs) are typically regarded as chemosensors that control cellular states in response to soluble extracellular cues. However, the modality of stimuli recognized through adhesion GPCR (aGPCR), the second largest class of the GPCR superfamily, is unresolved. Our study characterizes the Drosophila aGPCR Latrophilin/dCirl, a prototype member of this enigmatic receptor class. We show that dCirl shapes the perception of tactile, proprioceptive, and auditory stimuli through chordotonal neurons, the principal mechanosensors of Drosophila. dCirl sensitizes these neurons for the detection of mechanical stimulation by amplifying their input-output function. Our results indicate that aGPCR may generally process and modulate the perception of mechanical signals, linking these important stimuli to the sensory canon of the GPCR superfamily.}, language = {en} } @article{EhmannSauerKittel2015, author = {Ehmann, Nadine and Sauer, Markus and Kittel, Robert J.}, title = {Super-resolution microscopy of the synaptic active zone}, series = {Frontiers in Cellular Neuroscience}, volume = {9}, journal = {Frontiers in Cellular Neuroscience}, number = {7}, doi = {10.3389/fncel.2015.00007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148997}, year = {2015}, abstract = {Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ) a variety of specialized proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission. Calcium channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modeling approaches has provided predictions of channel properties, numbers and even positions on the nanometer scale. However, elucidating the nanoscopic organization of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy (SRM) techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how SRM can be used to obtain information on the organization of AZ proteins}, language = {en} } @article{HoffmannEtzrodtWillkommetal.2015, author = {Hoffmann, Linda S. and Etzrodt, Jennifer and Willkomm, Lena and Sanyal, Abhishek and Scheja, Ludger and Fischer, Alexander W. C. and Stasch, Johannes-Peter and Bloch, Wilhelm and Friebe, Andreas and Heeren, Joerg and Pfeifer, Alexander}, title = {Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {7235}, doi = {10.1038/ncomms8235}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143127}, year = {2015}, abstract = {Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing \(\beta\)\(_{1}\)-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.}, language = {en} }