Lehrstuhl für Physiologie

Schwerpunkt Neurophysiologie


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Lehrstuhl für Physiologie - Schwerpunkt Neurophysiologie


Vorstand: Prof. Dr. Manfred Heckmann

Ausgewählte Publikationen

Backhaus P, Langenhan T, Neuser K (2016)

J Neurogenet 30:22-31

Clostridial neurotoxins (botulinum toxins and tetanus toxin) disrupt neurotransmitter release by cleaving neuronal SNARE proteins. We generated transgenic flies allowing for conditional expression of different botulinum toxins and evaluated their potential as tools for the analysis of synaptic and neuronal network function in Drosophila melanogaster by applying biochemical assays and behavioral analysis. On the biochemical level,...

Kittel RJ, Heckmann M (2016)

Front Synaptic Neurosci 8:8

Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling...

Langenhan T, Piao X, Monk KR (2016)

Nat Rev Neurosci 17:550-561

Members of the adhesion G protein-coupled receptor (aGPCR) class have emerged as crucial regulators of nervous system development, with important implications for human health and disease. In this Review, we discuss the current understanding of aGPCR functions during key steps in neural development, including cortical patterning, dendrite and synapse formation, and myelination. We focus on aGPCR modulation of cell-cell and...

Werner C, Pauli M, Doose S, Weishaupt A, Haselmann H, Grünewald B, Sauer M, Heckmann M, Toyka KV, Asan E, Sommer C, Geis C (2016)

Brain 139:365-79

Stiff-person syndrome is the prototype of a central nervous system disorder with autoantibodies targeting presynaptic antigens. Patients with paraneoplastic stiff-person syndrome may harbour autoantibodies to the BAR (Bin/Amphiphysin/Rvs) domain protein amphiphysin, which target its SH3 domain. These patients have neurophysiological signs of...

Hamann J, Aust G, Arac D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin H-H, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB (2015)

Pharmacol Rev 67:338–367

CThe Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs...

Kollert S, Dombert B, Döring F, Wischmeyer E (2015)

Sci Rep 5:12548

In dorsal root ganglia (DRG) neurons TRESK channels constitute a major current component of the standing outward current IKSO. 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...

Paul MM, Pauli M, Ehmann N, Hallermann S, Sauer M, Kittel RJ, Heckmann M (2015)

Front Cell Neurosci 9:29

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...

Scholz N, Gehring J, Guan C, Ljaschenko D, Fischer R, Lakshmanan V, Kittel RJ, Langenhan T (2015)

Cell Reports 11:866-874

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...

Wagner N, Laugks U, Heckmann M, Asan E, Neuser K (2015)

J Comp Neurol 523:2457-75

Although age-related changes in synaptic plasticity are an important focus within neuroscience, little is known about ultrastructural changes of synaptic morphology during aging. Here we report how aging affects synaptic ultrastructure by using fluorescence and electron microscopy at the adult Drosophila neuromuscular junction (NMJ) of ventral abdominal muscles. Mainly four striking morphological changes of...

Dawydow A, Gueta R, Ljaschenko D, Ullrich S, Hermann M, Ehmann N, Gao S, Fiala A, Langenhan T, Nagel G, Kittel RJ (2014)

Proc Natl Acad Sci USA 111:13972-13977

Channelrhodopsin-2 (ChR2) has provided a breakthrough for the optogenetic control of neuronal activity. In adult Drosophila melanogaster, however, its applications are severely constrained. This limitation in a powerful model system has curtailed unfolding the full potential of ChR2 for behavioral neuroscience. Here, we describe the...

Ehmann N, van de Linde S, Alon A, Ljaschenko D, Keung XZ, Holm T, Rings A, DiAntonio A, Hallermann S, Ashery U, Heckmann M, Sauer M, Kittel RJ (2014)

Nat Commun 5:4650

The precise molecular architecture of synaptic active zones (AZs) gives rise to different structural and functional AZ states that fundamentally shape chemical neurotransmission. However, elucidating the nanoscopic protein arrangement at AZs is impeded by the diffraction-limited resolution of conventional light microscopy. Here...

Stock P, Ljaschenko D, Heckmann M, Dudel J (2014)

J Physiol 592:2501-2517

"Embryonic" muscle type nicotinic acetylcholine receptor-channels (nAChRs) bind ligands at interfaces of α- and of γ- or δ-subunits. αγ- and αδ-sites differ in affinity but their contributions in opening the channel remained elusive. We compared high resolution patch-clamp currents evoked by epibatidine (Ebd), carbamylcholine (CCh) and acetylcholine (ACh). Ebd binds with 75-fold higher affinity at αγ- than at...

Langenhan T, Aust G, Hamann J (2013)

Science Signaling 6(276):re3

Adhesion-type heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (Adhesion-GPCRs) comprise a class of widely distributed seven-transmembrane spanning (7TM) receptors with unusual layout and properties. The key to understanding the function of Adhesion-GPCRs appears to be their hybrid architecture: They have an extracellular domain containing an extended array of protein folds fit for interactions,...

Schmidt H, Brachtendorf S, Arendt O, Hallermann S, Ishiyama S, Bornschein G, Gall D,Schiffmann SN, Heckmann M, Eilers J (2013)

Current Biology 23:1-6

The coupling distance between presynaptic Ca2+ influx and the sensor for vesicular transmitter release determines speed and reliability of synaptic transmission [. Nanodomain coupling (<100 nm) favors fidelity and is employed by synapses specialized for escape reflexes and by inhibitory synapses involved in synchronizing fast network...

Stetter C, Hirschberg M, Nieswandt B, Ernestus RI, Heckmann M, Sirén AL (2013)

Exp Transl Stroke Med 5:9

INTRODUCTION: Structural plasticity with synapse formation and elimination is a key component of memory capacity and may be critical for functional recovery after brain injury. Here we describe in detail two surgical techniques to create a cranial window in mice and show crucial points in the procedure for long-term repeated in vivo imaging of synaptic structural plasticity in the mouse...

Wolber W, Ahmad R, Choi SW, Eckardt S, McLaughlin KJ, Schmitt J, Geis C, Heckmann M, Sirén AL, Müller AM (2013)

Cell Med 5:29-42

Uniparental zygotes with two paternal (androgenetic, AG) or two maternal genomes (gynogenetic, GG) cannot develop into viable offsprings but form blastocysts from which pluripotent embryonic stem (ES) cells can be derived. For most organs, it is unclear whether uniparental ES cells can give rise to stably expandable somatic stem cells that can repair injured...

Ahmad R, Wolber W, Eckardt S, Koch P, Schmitt J, Semechkin R, Geis C, Heckmann M, Brüstle O, McLaughlin JK, Sirén AL, Müller AM (2012)

PLoS One 7:e42800

Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural...

Prömel S, Waller-Evans H, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MBL, Grosse J, Schöneberg T, Russ AP, Langenhan T (2012)

Dev Dyn 241:1591-1602

We have studied evolution, expression and function of an entire receptor group containing four uncharacterized aGPCR: Gpr110, Gpr111, Gpr115 and Gpr116. We show that the genomic loci of these four receptors are clustered tightly together in mouse and human genomes and that this cluster likely derives from a single common ancestor gene. Using...

Prömel S, Frickenhaus M, Hughes S, Mestek L, Staunton D, Woollard A, Vakonakis I, Schöneberg T, Schnabel R, Russ AP, Langenhan T (2012)

Cell Reports 2:1-11

Adhesion class G protein-coupled receptors (aGPCR) form the second largest group of seven-transmembrane-spanning (7TM) receptors whose molecular layout and function differ from canonical 7TM receptors. Despite their essential roles in immunity, tumorigenesis, and development, the mechanisms of aGPCR activation and signal transduction have...

Froese A, Breher SS, Waldeyer C,2 Schindler RFR, Nikolaev VO, Rinné S, Wischmeyer E, Schlueter J, Becher J, Simrick S, Vauti F, Kuhtz J, Meister P, Kreissl S, Torlopp A, Liebig SK, Laakmann S, Müller TD, Neumann J, Stieber J, Ludwig A, Maier SK, Decher N, Arnold HH, Kirchhof P, Fabritz L, Brand T (2012)

J Clin Invest. 122:1119-1130

Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the...

Renner U, Zeug A, Woehler A, Niebert M, Dityatev A, Dityateva G, Gorinski N, Guseva D, Abdel-Galil D, Fröhlich M, Döring F, Wischmeyer E, Richter DW, Neher E, Ponimaskin EG (2012)

J Cell Sci. 125:2486-2499

Serotonin receptors 5-HT(1A) and 5-HT(7) are highly co-expressed in brain regions implicated in depression. However, their functional interaction has not been established. In the present study we show that 5-HT(1A) and 5-HT(7) receptors form heterodimers both in vitro and in vivo. Foerster...

Eckert M, Egenberger B, Döring F, Wischmeyer E (2011)

Neuropharmacology 61:918-923

Two-pore-domain K+ (K2P) channels are highly expressed in neurons and cardiac myocytes. In this study we investigated the potency of the antidepressant fluoxetine to inhibit brain and cardiac K2P channels, TREK-1, TASK-1 and THIK-1. Maximal sensitivity was detected for TREK-1, which was inhibited by 77% when expressed in HEK-293 cells and Xenopus oocytes. Alternative translation initiation (ATI) generates two...

Geis C, Weishaupt A, Grünewald B, Wultsch T, Reif A, Gerlach M, Dirkx R, Solimena M, Perani D, Heckmann M, Toyka KV, Folli F, Sommer C (2011)

PLoS One 6:e16775

BACKGROUND:Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior  can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle...

Riemensperger T, Isabel G, Coulom H, Neuser K, Seugnet L, Kume K, Iché-Torres M, Cassar M, Strauss R, Preat T, Hirsh J, Birman S (2011)

Proc Natl Acad Sci U S A. 108:834-839

The neuromodulatory function of dopamine (DA) is an inherent feature of nervous systems of all animals. To learn more about the function of neural DA in Drosophila, we generated mutant flies that lack tyrosine hydroxylase, and thus DA biosynthesis, selectively in the nervous system. We found that DA is absent or below...

Weyhersmüller A, Hallermann S, Wagner N, Eilers J (2011)

J Neurosci. 31: 6041-6052

How can synapses change the amount of neurotransmitter released during synaptic plasticity? Although release in general is intensely investigated, its determinants during plasticity are still poorly understood. As a model for plastic strengthening of synaptic release, we here use the well-established presynaptic homeostatic compensation during interference with postsynaptic glutamate receptors at the Drosophila...

Egenberger  B, Polleichtner G, Wischmeyer  E,  Döring F (2010)

Biochem. Biophys. Res. Commun. 391:12672-12677

Within the first external loop of mouse and human TRESK subunits one or two N-glycosylation consensus sites were identified, respectively. Using site directed mutagenesis and Western immunoblotting a single residue of both orthologues was found to be glycosylated upon heterologous expression. Two-electrode voltage-clamp recordings from Xenopus oocytes revealed that...

Geis C, Weishaupt A, Hallermann S, Grünewald B, Wessig C, Wultsch T, Reif A, Byts N, Beck M, Jablonka S, Boettger MK, Üçeyler N, Fouquet W, Gerlach M, Meinck HM, Sirén AL, Sigrist SJ, Toyka KV, Heckmann M*, Sommer C* (2010) (* equal contribution)

Brain 133:3166-3180

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...

Hallermann S, Heckmann M, Kittel RJ (2010)

HFSP J 4:72-84

During short bursts of neuronal activity, changes in the efficacy of neurotransmitter release are governed primarily by two counteracting processes: (1) Ca(2+)-dependent elevations of vesicle release probability and (2) depletion of synaptic vesicles. The dynamic interplay of both processes contributes to the expression of activity-dependent synaptic plasticity. Here, we exploited various facets of short-term plasticity at the...

Hallermann S*, Kittel RJ*, Wichmann C*, Weyhersmüller A, Fouquet W, Mertel S, Owald D, Eimer S, Depner H, Schwärzel M, Sigrist SJ, Heckmann M (2010) (* geteilte Erstautorenschaft)

J Neurosci 30:14340-14345

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...

Kleene R,  Cassens C, Bähring, R, Thei, T, Xiang M,  Xu J, Dityatev A,  Schafer-Nielsen C,  Döring F,  Wischmeyer E, Schachner M (2010)

J. Biol. Chem. 285:28968-28979

Cell adhesion molecules and neurotrophin receptors are crucial for the development and the function of the nervous system. Among downstream effectors of neurotrophin receptors and recognition molecules are ion channels. Here, we provide evidence that G protein-coupled inwardly rectifying K(+) channel...

Langenhan T, Russ AP (2010)

1st ed. Yona S, Stacey M, eds. Austin/New York: Landes Bioscience/Springer Science+Business Media. Adv Exp Med Biol 706

Understanding the mechanisms that coordinate the polarity of cells and tissues during embryogenesis and morphogenesis is a fundamental problem in developmental biology. We have recently demonstrated that the putative neurotoxin receptor lat-1 defines a mechanism required for the alignment of cell division planes in the early embryo of the nematode...

McGuinness L, Taylor C, Taylor RDT, Yau C, Langenhan T, Hart ML, Christian H, Tynan PW, Donnelly P, Emptage NJ (2010)

Neuron 68:1109-1127

A rise in [Ca(2+)](i) provides the trigger for neurotransmitter release at neuronal boutons. We have used confocal microscopy and Ca(2+) sensitive dyes to directly measure the action potential-evoked [Ca(2+)](i) in the boutons of Schaffer collaterals. This reveals that the trial-by-trial amplitude of the evoked Ca(2+) transient is bimodally distributed. We...

Triphan T, Poeck B, Neuser K, Strauss R. (2010)

Curr Biol. 20:663-668

Drosophila melanogaster flies cross surmountable gaps in their walkway of widths exceeding their body length with an astounding maneuver but avoid attempts at insurmountable gaps by visual width estimation. Different mutant lines affect specific aspects of this maneuver, indicating a high complexity and modularity of the underlying motor control. Here we report on two mutants, ocelliless(1) and tay bridge(1), that,...