Recent Submissions

  • Journal Article

    A novel method for culturing stellate astrocytes reveals spatially distinct Ca2+ signaling and vesicle recycling in astrocytic processes. 

    Wolfes, Anne C.; Ahmed, Saheeb; Awasthi, Ankit; Stahlberg, Markus A.; Rajput, Ashish; Magruder, Daniel S.; Bonn, Stefan; Dean, Camin
    The Journal of general physiology 2017; 149(1) p.149-170
    Interactions between astrocytes and neurons rely on the release and uptake of glial and neuronal molecules. But whether astrocytic vesicles exist and exocytose in a regulated or constitutive fashion is under debate. The majority of studies have relied on indirect methods or on astrocyte cultures that do not resemble stellate astrocytes found in vivo. Here, to investigate vesicle-associated proteins and exocytosis in stellate astrocytes specifically, we developed a simple, fast, and economical method for growing stellate astrocyte monocultures. This method is superior to other monocultures in terms of astrocyte morphology, mRNA expression profile, protein expression of cell maturity markers, and Ca(2+) fluctuations: In astrocytes transduced with GFAP promoter-driven Lck-GCaMP3, spontaneous Ca(2+) events in distinct domains (somata, branchlets, and microdomains) are similar to those in astrocytes co-cultured with other glia and neurons but unlike Ca(2+) events in astrocytes prepared using the McCarthy and de Vellis (MD) method and immunopanned (IP) astrocytes. We identify two distinct populations of constitutively recycling vesicles (harboring either VAMP2 or SYT7) specifically in branchlets of cultured stellate astrocytes. SYT7 is developmentally regulated in these astrocytes, and we observe significantly fewer synapses in wild-type mouse neurons grown on Syt7(-/-) astrocytes. SYT7 may thus be involved in trafficking or releasing synaptogenic factors. In summary, our novel method yields stellate astrocyte monocultures that can be used to study Ca(2+) signaling and vesicle recycling and dynamics in astrocytic processes.
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  • Journal Article

    Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis 

    Fernández-Mosquera, Lorena; Diogo, Cátia V.; Yambire, King Faisal; Santos, Gabriela L.; Luna Sánchez, Marta; Bénit, Paule; Rustin, Pierre; Lopez, Luis Carlos; Milosevic, Ira; Raimundo, Nuno
    Scientific Reports 2017; 7: Art. 45076
    Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline. Long-term RC inhibition by long-term treatment with rotenone, or patient mutations in fibroblasts and in a mouse model result in repression of lysosomal biogenesis. The induction of lysosomal biogenesis by short-term mitochondrial stress is dependent on TFEB and MITF, requires AMPK signaling and is independent of calcineurin signaling. These results reveal an integrated view of how mitochondrial signaling affects lysosomes, which is essential to fully comprehend the consequences of mitochondrial malfunction, particularly in the context of mitochondrial diseases.
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  • Journal Article

    Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits 

    Burk, Katja; Mire, Erik; Bellon, Anaïs; Hocine, Mélanie; Guillot, Jeremy; Moraes, Filipa; Yoshida, Yutaka; Simons, Michael; Chauvet, Sophie; Mann, Fanny
    Nature Communications 2017; 8: Art. 14508
    Local endocytic events involving receptors for axon guidance cues play a central role in controlling growth cone behaviour. Yet, little is known about the fate of internalized receptors, and whether the sorting events directing them to distinct endosomal pathways control guidance decisions. Here, we show that the receptor Plexin-D1 contains a sorting motif that interacts with the adaptor protein GIPC1 to facilitate transport to recycling endosomes. This sorting process promotes colocalization of Plexin-D1 with vesicular pools of active R-ras, leading to its inactivation. In the absence of interaction with GIPC1, missorting of Plexin-D1 results in loss of signalling activity. Consequently, Gipc1 mutant mice show specific defects in axonal projections, as well as vascular structures, that rely on Plexin-D1 signalling for their development. Thus, intracellular sorting steps that occur after receptor internalization by endocytosis provide a critical level of control of cellular responses to guidance signals.
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  • Journal Article

    Visual attention is available at a task-relevant location rapidly after a saccade 

    Yao, Tao; Ketkar, Madhura; Treue, Stefan; Krishna, B. Suresh
    eLife 2016; 5: Art. e18009
    Maintaining attention at a task-relevant spatial location while making eye-movements necessitates a rapid, saccade-synchronized shift of attentional modulation from the neuronal population representing the task-relevant location before the saccade to the one representing it after the saccade. Currently, the precise time at which spatial attention becomes fully allocated to the task-relevant location after the saccade remains unclear. Using a fine-grained temporal analysis of human peri-saccadic detection performance in an attention task, we show that spatial attention is fully available at the task-relevant location within 30 milliseconds after the saccade. Subjects tracked the attentional target veridically throughout our task: i.e. they almost never responded to non-target stimuli. Spatial attention and saccadic processing therefore co-ordinate well to ensure that relevant locations are attentionally enhanced soon after the beginning of each eye fixation.
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  • Journal Article

    Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System 

    Murdoch, John D.; Rostosky, Christine M.; Gowrisankaran, Sindhuja; Arora, Amandeep S.; Soukup, Sandra-Fausia; Vidal, Ramon; Capece, Vincenzo; Freytag, Siona; Fischer, Andre; Verstreken, Patrik; et al.
    Bonn, StefanRaimundo, NunoMilosevic, Ira
    Cell Reports 2016; 17(4) p.1071-1086
    Endophilin-A, a well-characterized endocytic adaptor essential for synaptic vesicle recycling, has recently been linked to neurodegeneration. We report here that endophilin-A deficiency results in impaired movement, age-dependent ataxia, and neurodegeneration in mice. Transcriptional analysis of endophilin- A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A. FBXO32 overexpression triggers apoptosis in cultured cells and neurons but, remarkably, coexpression of endophilin-A rescues it. FBXO32 interacts with all three endophilin-A proteins. Similarly to endophilin-A, FBXO32 tubulates membranes and localizes on clathrin-coated structures. Additionally, FBXO32 and endophilin-A are necessary for autophagosome formation, and both colocalize transiently with autophagosomes. Our results point to a role for endophilin-A proteins in autophagy and protein degradation, processes that are impaired in their absence, potentially contributing to neurodegeneration and ataxia.
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  • Journal Article

    The SocioBox: A Novel Paradigm to Assess Complex Social Recognition in Male Mice. 

    Krueger-Burg, Dilja; Winkler, Daniela; Mitkovski, Mišo; Daher, Fernanda; Ronnenberg, Anja; Schlüter, Oliver M; Dere, Ekrem; Ehrenreich, Hannelore
    Frontiers in behavioral neuroscience 2016; 10: Art. 151
    Impairments in social skills are central to mental disease, and developing tools for their assessment in mouse models is essential. Here we present the SocioBox, a new behavioral paradigm to measure social recognition. Using this paradigm, we show that male wildtype mice of different strains can readily identify an unfamiliar mouse among 5 newly acquainted animals. In contrast, female mice exhibit lower locomotor activity during social exploration in the SocioBox compared to males and do not seem to discriminate between acquainted and unfamiliar mice, likely reflecting inherent differences in gender-specific territorial tasks. In addition to a simple quantification of social interaction time of mice grounded on predefined spatial zones (zone-based method), we developed a set of unbiased, data-driven analysis tools based on heat map representations and characterized by greater sensitivity. First proof-of-principle that the SocioBox allows diagnosis of social recognition deficits is provided using male PSD-95 heterozygous knockout mice, a mouse model related to psychiatric pathophysiology.
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  • Journal Article

    IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses. 

    Gazit, Neta; Vertkin, Irena; Shapira, Ilana; Helm, Martin; Slomowitz, Edden; Sheiba, Maayan; Mor, Yael; Rizzoli, Silvio; Slutsky, Inna
    Neuron 2016-02-03; 89(3) p.583-597
    The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer's disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca(2+) transients, while promoting spontaneous transmission and resting Ca(2+) level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca(2+) buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer's disease. VIDEO ABSTRACT.
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  • Journal Article

    Retinal Remodeling: Concerns, Emerging Remedies and Future Prospects. 

    Krishnamoorthy, Vidhyasankar; Cherukuri, Pitchaiah; Poria, Deepak; Goel, Manvi; Dagar, Sushma; Dhingra, Narender K.
    Frontiers in cellular neuroscience 2016; 10: Art. 38
    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.
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  • Journal Article

    Ocular Dominance Plasticity after Stroke Was Preserved in PSD-95 Knockout Mice. 

    Greifzu, Franziska; Parthier, Daniel; Goetze, Bianka; Schlüter, Oliver M.; Löwel, Siegrid
    PloS one 2016; 11(3): Art. e0149771
    Neuronal plasticity is essential to enable rehabilitation when the brain suffers from injury, such as following a stroke. One of the most established models to study cortical plasticity is ocular dominance (OD) plasticity in the primary visual cortex (V1) of the mammalian brain induced by monocular deprivation (MD). We have previously shown that OD-plasticity in adult mouse V1 is absent after a photothrombotic (PT) stroke lesion in the adjacent primary somatosensory cortex (S1). Exposing lesioned mice to conditions which reduce the inhibitory tone in V1, such as raising animals in an enriched environment or short-term dark exposure, preserved OD-plasticity after an S1-lesion. Here we tested whether modification of excitatory circuits can also be beneficial for preserving V1-plasticity after stroke. Mice lacking postsynaptic density protein-95 (PSD-95), a signaling scaffold present at mature excitatory synapses, have lifelong juvenile-like OD-plasticity caused by an increased number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) -silent synapses in V1 but unaltered inhibitory tone. In fact, using intrinsic signal optical imaging, we show here that OD-plasticity was preserved in V1 of adult PSD-95 KO mice after an S1-lesion but not in PSD-95 wildtype (WT)-mice. In addition, experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both lesioned PSD-95 KO and PSD-95 WT mice. Basic V1-activation and retinotopic map quality were, however, not different between lesioned PSD-95 KO mice and their WT littermates. The preserved OD-plasticity in the PSD-95 KO mice indicates that V1-plasticity after a distant stroke can be promoted by either changes in excitatory circuitry or by lowering the inhibitory tone in V1 as previously shown. Furthermore, the present data indicate that an increased number of AMPA-silent synapses preserves OD-plasticity not only in the healthy brain, but also in another experimental paradigm of cortical plasticity, namely the long-range influence on V1-plasticity after an S1-lesion.
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  • Journal Article

    Dlk1 promotes a fast motor neuron biophysical signature required for peak force execution. 

    Müller, Daniel; Cherukuri, Pitchaiah; Henningfeld, Kristine; Poh, Chor Hoon; Wittler, Lars; Grote, Phillip; Schlüter, Oliver; Schmidt, Jennifer; Laborda, Jorge; Bauer, Steven R.; et al.
    Brownstone, Robert M.Marquardt, Till
    Science 2014-03-14; 343 p.1264-1266: Art. 6176
    Motor neurons, which relay neural commands to drive skeletal muscle movements, encompass types ranging from "slow" to "fast," whose biophysical properties govern the timing, gradation, and amplitude of muscle force. Here we identify the noncanonical Notch ligand Delta-like homolog 1 (Dlk1) as a determinant of motor neuron functional diversification. Dlk1, expressed by ~30% of motor neurons, is necessary and sufficient to promote a fast biophysical signature in the mouse and chick. Dlk1 suppresses Notch signaling and activates expression of the K(+) channel subunit Kcng4 to modulate delayed-rectifier currents. Dlk1 inactivation comprehensively shifts motor neurons toward slow biophysical and transcriptome signatures, while abolishing peak force outputs. Our findings provide insights into the development of motor neuron functional diversity and its contribution to the execution of movements.
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  • Journal Article

    Sequence Analysis and Identification of New Isoform of EP4 Receptors in Different Atlantic Salmon Tissues (Salmo salar L.) and Its Role in PGE2 Induced Immunomodulation In Vitro. 

    Guo, Tz Chun; Gamil, Amr Ahmed Abdelrahim; Koenig, Melanie; Evensen, Øystein
    PloS one 2015; 10(3) p.1-e0120483: Art. e0120483
    PGE2 plays an important role in a broad spectrum of physiological and pathological processes mediated through a membrane-bound G protein-coupled receptor (GPCR) called EP receptor. In mammals, four subtypes of EP receptor (EP 1-4) are identified and each of them functions through different signal transduction pathways. Orthologous EP receptors have also been identified in other non-mammalian species, such as chicken and zebrafish. EP4 is the only identified PGE2 receptor to date in Atlantic salmon but its tissue distribution and function have not been studied in any detail. In this study, we first sequenced EP4 receptor in different tissues and found that the presence of the 3nt deletion in the 5' untranslated region was accompanied by silent mutation at nt 668. While attempting to amplify the same sequence in TO cells (an Atlantic salmon macrophage-like cell line), we failed to obtain the full-length product. Further investigation revealed different isoform of EP4 receptor in TO cells and we subsequently documented its presence in different Atlantic salmon tissues. These two isoforms of EP4 receptor share high homology in their first half of sequence but differ in the second half part with several deletion segments though the final length of coding sequence is the same for two isoforms. We further studied the immunomodulation effect of PGE2 in TO cells and found that PGE2 inhibited the induction of CXCL-10, CCL-4, IL-8 and IL-1β genes expression in a time dependent manner and without cAMP upregulation.
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  • Journal Article

    Vesicle uncoating regulated by SH3-SH3 domain-mediated complex formation between endophilin and intersectin at synapses. 

    Pechstein, Arndt; Gerth, Fabian; Milosevic, Ira; Jäpel, Maria; Eichhorn-Grünig, Marielle; Vorontsova, Olga; Bacetic, Jelena; Maritzen, Tanja; Shupliakov, Oleg; Freund, Christian; et al.
    Haucke, Volker
    EMBO reports 2015-02-01; 16(2) p.232-9
    Neurotransmission involves the exo-endocytic cycling of synaptic vesicle (SV) membranes. Endocytic membrane retrieval and clathrin-mediated SV reformation require curvature-sensing and membrane-bending BAR domain proteins such as endophilin A. While their ability to sense and stabilize curved membranes facilitates membrane recruitment of BAR domain proteins, the precise mechanisms by which they are targeted to specific sites of SV recycling has remained unclear. Here, we demonstrate that the multi-domain scaffold intersectin 1 directly associates with endophilin A to facilitate vesicle uncoating at synapses. Knockout mice deficient in intersectin 1 accumulate clathrin-coated vesicles at synapses, a phenotype akin to loss of endophilin function. Intersectin 1/endophilin A1 complex formation is mediated by direct binding of the SH3B domain of intersectin to a non-canonical site on the SH3 domain of endophilin A1. Consistent with this, intersectin-binding defective mutant endophilin A1 fails to rescue clathrin accumulation at neuronal synapses derived from endophilin A1-3 triple knockout (TKO) mice. Our data support a model in which intersectin aids endophilin A recruitment to sites of clathrin-mediated SV recycling, thereby facilitating vesicle uncoating.
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  • Journal Article

    Histone-acetylation: a link between Alzheimer's disease and post-traumatic stress disorder? 

    Bahari-Javan, Sanaz; Sananbenesi, Farahnaz; Fischer, Andre
    Frontiers in neuroscience 2014; 8 p.1-7: Art. 160
    The orchestration of gene-expression programs is essential for cellular homeostasis. Epigenetic processes provide to the cell a key mechanism that allows the regulation of gene-expression networks in response to environmental stimuli. Recently epigenetic mechanisms such as histone-modifications have been implicated with cognitive function and altered epigenome plasticity has been linked to the pathogenesis of neurodegenerative and neuropsychiatric diseases. Thus, key regulators of epigenetic gene-expression have emerged as novel drug targets for brain diseases. Numerous recent review articles discuss in detail the current findings of epigenetic processes in brain diseases. The aim of this article is not to give yet another comprehensive overview of the field but to specifically address the question why the same epigenetic therapies that target histone-acetylation may be suitable to treat seemingly different diseases such as Alzheimer's disease and post-traumatic stress disorder.
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  • Journal Article

    BDNF enhances spontaneous and activity-dependent neurotransmitter release at excitatory terminals but not at inhibitory terminals in hippocampal neurons. 

    Shinoda, Yo; Ahmed, Saheeb; Ramachandran, Binu; Bharat, Vinita; Brockelt, David; Altas, Bekir; Dean, Camin
    Frontiers in synaptic neuroscience 2014; 6: Art. 27
    Brain-derived neurotrophic factor (BDNF) is widely reported to enhance synaptic vesicle (SV) exocytosis and neurotransmitter release. But it is still unclear whether BDNF enhances SV recycling at excitatory terminals only, or at both excitatory and inhibitory terminals. In the present study, in a direct comparison using cultured rat hippocampal neurons, we demonstrate that BDNF enhances both spontaneous and activity-dependent neurotransmitter release from excitatory terminals, but not from inhibitory terminals. BDNF treatment for 5 min or 48 h increased both spontaneous and activity-induced anti-synaptotagmin1 (SYT1) antibody uptake at excitatory terminals marked with vGluT1. Conversely, BDNF treatment did not enhance spontaneous or activity-induced uptake of anti-SYT1 antibodies in inhibitory terminals marked with vGAT. Time-lapse imaging of FM1-43 dye destaining in excitatory and inhibitory terminals visualized by post-hoc immunostaining of vGluT1 and vGAT also showed the same result: The rate of spontaneous and activity-induced destaining was increased by BDNF at excitatory synapses, but not at inhibitory synapses. These data demonstrate that BDNF enhances SV exocytosis in excitatory but not inhibitory terminals. Moreover, BDNF enhanced evoked SV exocytosis, even if vesicles were loaded under spontaneous vesicle recycling conditions. Thus, BDNF enhances both spontaneous and activity-dependent neurotransmitter release on both short and long time-scales, by the same mechanism.
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  • Journal Article

    What axons tell each other: axon-axon signaling in nerve and circuit assembly. 

    Wang, Liang; Marquardt, Till
    Current opinion in neurobiology 2013-12-01; 23(6) p.974-982
    A remarkable feature of nervous system development is the ability of axons emerging from newly formed neurons to traverse, by cellular scale, colossal distances to appropriate targets. The earliest axons achieve this in an essentially axon-free environment, but the vast majority of axons eventually grow along a scaffold of nerve tracts created by earlier extending axons. Signal exchange between sequentially or simultaneously extending axons may well represent the predominant mode of axonal navigation, but proportionally few efforts have so far been directed at deciphering the underlying mechanisms. This review intends to provide a conceptual update on the cellular and molecular principles driving axon-axon interactions, with emphasis on those contributing to the fidelity of axonal navigation, sorting and connectivity during nerve and circuit assembly.
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  • Journal Article

    Muscle dystroglycan organizes the postsynapse and regulates presynaptic neurotransmitter release at the Drosophila neuromuscular junction. 

    Bogdanik, Laurent; Framery, Bérénice; Frölich, Andreas; Franco, Bénédicte; Mornet, Dominique; Bockaert, Joël; Sigrist, Stephan J.; Grau, Yves; Parmentier, Marie-Laure
    PloS one 2008; 3(4): Art. e2084
    BACKGROUND: The Dystrophin-glycoprotein complex (DGC) comprises dystrophin, dystroglycan, sarcoglycan, dystrobrevin and syntrophin subunits. In muscle fibers, it is thought to provide an essential mechanical link between the intracellular cytoskeleton and the extracellular matrix and to protect the sarcolemma during muscle contraction. Mutations affecting the DGC cause muscular dystrophies. Most members of the DGC are also concentrated at the neuromuscular junction (NMJ), where their deficiency is often associated with NMJ structural defects. Hence, synaptic dysfunction may also intervene in the pathology of dystrophic muscles. Dystroglycan is a central component of the DGC because it establishes a link between the extracellular matrix and Dystrophin. In this study, we focused on the synaptic role of Dystroglycan (Dg) in Drosophila. METHODOLOGY/PRINCIPAL FINDINGS: We show that Dg was concentrated postsynaptically at the glutamatergic NMJ, where, like in vertebrates, it controls the concentration of synaptic Laminin and Dystrophin homologues. We also found that synaptic Dg controlled the amount of postsynaptic 4.1 protein Coracle and alpha-Spectrin, as well as the relative subunit composition of glutamate receptors. In addition, both Dystrophin and Coracle were required for normal Dg concentration at the synapse. In electrophysiological recordings, loss of postsynaptic Dg did not affect postsynaptic response, but, surprisingly, led to a decrease in glutamate release from the presynaptic site. CONCLUSION/SIGNIFICANCE: Altogether, our study illustrates a conservation of DGC composition and interactions between Drosophila and vertebrates at the synapse, highlights new proteins associated with this complex and suggests an unsuspected trans-synaptic function of Dg.
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  • Journal Article

    TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. 

    Takahashi, Kazuya; Prinz, Marco; Stagi, Massimiliano; Chechneva, Olga; Neumann, Harald
    PLoS medicine 2007-04-01; 4(4): Art. e124
    BACKGROUND: In multiple sclerosis, inflammation can successfully be prevented, while promoting repair is still a major challenge. Microglial cells, the resident phagocytes of the central nervous system (CNS), are hematopoietic-derived myeloid cells and express the triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor. Myeloid cells are an accessible source for ex vivo gene therapy. We investigated whether myeloid precursor cells genetically modified to express TREM2 affect the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. METHODS AND FINDINGS: EAE was induced in mice by immunization with a myelin autoantigen. Intravenous application of TREM2-transduced bone marrow-derived myeloid precursor cells at the EAE peak led to an amelioration of clinical symptoms, reduction in axonal damage, and prevention of further demyelination. TREM2-transduced myeloid cells applied intravenously migrated into the inflammatory spinal cord lesions of EAE-diseased mice, showed increased lysosomal and phagocytic activity, cleared degenerated myelin, and created an anti-inflammatory cytokine milieu within the CNS. CONCLUSIONS: Intravenously applied bone marrow-derived and TREM2-tranduced myeloid precursor cells limit tissue destruction and facilitate repair within the murine CNS by clearance of cellular debris during EAE. TREM2 is a new attractive target for promotion of repair and resolution of inflammation in multiple sclerosis and other neuroinflammatory diseases.
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  • Journal Article

    “Self” versus “Non-Self” Connectivity Dictates Properties of Synaptic Transmission and Plasticity 

    Liu, Huisheng; Chapman, Edwin R.; Dean, Camin
    PLoS ONE 2013-04-29; 8(4): Art. e62414
    Autapses are connections between a neuron and itself. These connections are morphologically similar to ‘‘normal’’ synapses between two different neurons, and thus were long thought to have similar properties of synaptic transmission. However, this has not been directly tested. Here, using a micro-island culture assay in which we can define the number of interconnected cells, we directly compared synaptic transmission in excitatory autapses and in two-neuron micronetworks consisting of two excitatory neurons, in which a neuron is connected to one other neuron and to itself. We discovered that autaptic synapses are optimized for maximal transmission, and exhibited enhanced EPSC amplitude, charge, and RRP size compared to interneuronal synapses. However, autapses are deficient in several aspects of synaptic plasticity. Short-term potentiation only became apparent when a neuron was connected to another neuron. This acquisition of plasticity only required reciprocal innervation with one other neuron; micronetworks consisting of just two interconnected neurons exhibited enhanced short-term plasticity in terms of paired pulse ratio (PPR) and release probability (Pr), compared to autapses. Interestingly, when a neuron was connected to another neuron, not only interneuronal synapses, but also the autaptic synapses on itself exhibited a trend toward enhanced short-term plasticity in terms of PPR and Pr. Thus neurons can distinguish whether they are connected via ‘‘self’’ or ‘‘non-self’’ synapses and have the ability to adjust their plasticity parameters when connected to other neurons.
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  • Journal Article

    Transcranial magnetic stimulation with a half-sine wave pulse elicits direction-specific effects in human motor cortex 

    Jung, Nikolai H.; Delvendahl, Igor; Pechmann, Astrid; Gleich, Bernhard; Gattinger, Norbert; Siebner, Hartwig R.; Mall, Volker
    BMC Neuroscience 2012; 13(1) p.139-148
    Background: Transcranial magnetic stimulation (TMS) commonly uses so-called monophasic pulses where the initial rapidly changing current flow is followed by a critically dampened return current. It has been shown that a monophasic TMS pulse preferentially excites different cortical circuits in the human motor hand area (M1-HAND), if the induced tissue current has a posterior-to-anterior (PA) or anterior-to-posterior (AP) direction. Here we tested whether similar direction-specific effects could be elicited in M1-HAND using TMS pulses with a half-sine wave configuration. Results: In 10 young participants, we applied half-sine pulses to the right M1-HAND which elicited PA or AP currents with respect to the orientation of the central sulcus. Measurements of the motor evoked potential (MEP) revealed that PA half-sine stimulation resulted in lower resting motor threshold (RMT) than AP stimulation. When stimulus intensity (SI) was gradually increased as percentage of maximal stimulator output, the stimulus–response curve (SRC) of MEP amplitude showed a leftward shift for PA as opposed to AP half-sine stimulation. Further, MEP latencies were approximately 1 ms shorter for PA relative to AP half-sine stimulation across the entire SI range tested. When adjusting SI to the respective RMT of PA and AP stimulation, the direction-specific differences in MEP latencies persisted, while the gain function of MEP amplitudes was comparable for PA and AP stimulation. Conclusions: Using half-sine pulse configuration, single-pulse TMS elicits consistent direction-specific effects in M1-HAND that are similar to TMS with monophasic pulses. The longer MEP latency for AP half-sine stimulation suggests that PA and AP half-sine stimulation preferentially activates different sets of cortical neurons that are involved in the generation of different corticospinal descending volleys. Keywords: Transcranial magnetic stimulation, Current direction, Half-sine stimulus, I-waves, Stimulus–response curves, Motor cortex * Correspondence: volker.mall@tum.de †Equal contributors 1Department of Pediatrics, Technical University Munich, Kinderzentrum München gemeinnützige GmbH, Heiglhofstrasse 63, Munich 81377, Germany 2Department of Paediatrics and Adolescent Medicine, Division of Neuropaediatrics and Muscular Disorders, University Medical Centre Freiburg, Mathildenstr 1, Freiburg 79106, Germany Full list of author information is available at the end of the article © 2012
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  • Journal Article

    HDAC1 Regulates Fear Extinction in Mice 

    Bahari-Javan, S.; Maddalena, A.; Kerimoglu, C.; Wittnam, J.; Held, T.; Bähr, M.; Burkhardt, S.; Delalle, I.; Kügler, S.; Fischer, A.; et al.
    Sananbenesi, F.
    Journal of Neuroscience 2012; 32(15) p.5062-5073
    Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function.
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