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    TORC1-mediated sensing of chaperone activity alters glucose metabolism and extends lifespan. 

    Perić, Matea; Lovrić, Anita; Šarić, Ana; Musa, Marina; Bou Dib, Peter; Rudan, Marina; Nikolić, Andrea; Sobočanec, Sandra; Mikecin, Ana-Matea; Dennerlein, Sven; et al.
    Milošević, IraVlahoviček, KristianRaimundo, NunoKriško, Anita
    Aging Cell 2017; 16(5) p.994-1005
    Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activity and consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age-related diseases.
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    Neurofeedback of Slow Cortical Potentials in Children with Attention-Deficit/Hyperactivity Disorder: A Multicenter Randomized Trial Controlling for Unspecific Effects. 

    Strehl, Ute; Aggensteiner, Pascal; Wachtlin, Daniel; Brandeis, Daniel; Albrecht, Björn; Arana, Maria; Bach, Christiane; Banaschewski, Tobias; Bogen, Thorsten; Flaig-Röhr, Andrea; et al.
    Freitag, Christine M.Fuchsenberger, YvonneGest, StephanieGevensleben, HolgerHerde, LauraHohmann, SarahLegenbauer, TanjaMarx, Anna-MariaMillenet, SabinaPniewski, BenjaminRothenberger, AribertRuckes, ChristianWörz, SonjaHoltmann, Martin
    Frontiers in human neuroscience 2017; 11: Art. 135
    Background: Neurofeedback (NF) in children with attention-deficit/hyperactivity disorder (ADHD) has been investigated in a series of studies over the last years. Previous studies did not unanimously support NF as a treatment in ADHD. Most studies did not control for unspecific treatment effects and did not demonstrate that self-regulation took place. The present study examined the efficacy of NF in comparison to electromyographic (EMG) feedback to control for unspecific effects of the treatment, and assessed self-regulation of slow cortical potentials (SCPs). Methods: A total of 150 children aged 7-9 years diagnosed with ADHD (82% male; 43% medicated) were randomized to 25 sessions of feedback of SCPs (NF) or feedback of coordination of the supraspinatus muscles (EMG). The primary endpoint was the change in parents' ratings of ADHD core symptoms 4 weeks after the end of treatment compared to pre-tests. Results: Children in both groups showed reduced ADHD-core symptoms (NF 0.3, 95% CI -0.42 to -0.18; EMG 0.13, 95% CI -0.26 to -0.01). NF showed a significant superiority over EMG (treatment difference 0.17, 95% CI 0.02-0.3, p = 0.02). This yielded an effect size (ES) of d = 0.57 without and 0.40 with baseline observation carried forward (BOCF). The sensitivity analysis confirmed the primary result. Successful self-regulation of brain activity was observed only in NF. As a secondary result teachers reported no superior improvement from NF compared to EMG, but within-group analysis revealed effects of NF on the global ADHD score, inattention, and impulsivity. In contrast, EMG feedback did not result in changes despite more pronounced self-regulation learning. Conclusions: Based on the primary parent-rated outcome NF proved to be superior to a semi-active EMG feedback treatment. The study supports the feasibility and efficacy of NF in a large sample of children with ADHD, based on both specific and unspecific effects. Trial Register: Current controlled trials ISRCTN76187185, registered 5 February 2009.
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    The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice. 

    Benito, E.; Ramachandran, B.; Schroeder, H.; Schmidt, G.; Urbanke, H.; Burkhardt, S.; Capece, V.; Dean, C.; Fischer, A.
    Translational psychiatry 2017-09-26; 7(9) p.e1239-e1239
    Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.
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    TRPV1 regulates excitatory innervation of OLM neurons in the hippocampus 

    Hurtado-Zavala, Joaquin I.; Ramachandran, Binu; Ahmed, Saheeb; Halder, Rashi; Bolleyer, Christiane; Awasthi, Ankit; Stahlberg, Markus A.; Wagener, Robin J.; Anderson, Kristin; Drenan, Ryan M.; et al.
    Lester, Henry A.Miwa, Julie M.Staiger, Jochen F.Fischer, AndreDean, Camin
    Nature communications 2017; 8: Art. 15878
    TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. However, the location and function of TRPV1 in the hippocampus is debated. We found that TRPV1 is expressed in oriens-lacunosum-moleculare (OLM) interneurons in the hippocampus, and promotes excitatory innervation. TRPV1 knockout mice have reduced glutamatergic innervation of OLM neurons. When activated by capsaicin, TRPV1 recruits more glutamatergic, but not GABAergic, terminals to OLM neurons in vitro. When TRPV1 is blocked, glutamatergic input to OLM neurons is dramatically reduced. Heterologous expression of TRPV1 also increases excitatory innervation. Moreover, TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine-via α2β2-containing nicotinic receptors-to bypass innervation defects. Our results reveal a synaptogenic function of TRPV1 in a specific interneuron population in the hippocampus, where it is important for gating hippocampal plasticity.
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    Capture of Dense Core Vesicles at Synapses by JNK-Dependent Phosphorylation of Synaptotagmin-4. 

    Bharat, Vinita; Siebrecht, Michael; Burk, Katja; Ahmed, Saheeb; Reissner, Carsten; Kohansal-Nodehi, Mahdokht; Steubler, Vicky; Zweckstetter, Markus; Ting, Jonathan T; Dean, Camin
    Cell reports 2017-11-21; 21(8) p.2118-2133
    Delivery of neurotrophins and neuropeptides via long-range trafficking of dense core vesicles (DCVs) from the cell soma to nerve terminals is essential for synapse modulation and circuit function. But the mechanism by which transiting DCVs are captured at specific sites is unknown. Here, we discovered that Synaptotagmin-4 (Syt4) regulates the capture and spatial distribution of DCVs in hippocampal neurons. We found that DCVs are highly mobile and undergo long-range translocation but switch directions only at the distal ends of axons, revealing a circular trafficking pattern. Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction, leading to a transition from microtubule-dependent DCV trafficking to capture at en passant presynaptic boutons by actin. Furthermore, neuronal activity increased DCV capture via JNK-dependent phosphorylation of the S135 site of Syt4. Our data reveal a mechanism that ensures rapid, site-specific delivery of DCVs to synapses.
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    EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons 

    Burk, Katja; Murdoch, John D.; Freytag, Siona; Koenig, Melanie; Bharat, Vinita; Markworth, Ronja; Burkhardt, Susanne; Fischer, Andre; Dean, Camin
    Scientific Reports 2017; 7(1): Art. 2149
    The sorting of activated receptors into distinct endosomal compartments is essential to activate specific signaling cascades and cellular events including growth and survival. However, the proteins involved in this sorting are not well understood. We discovered a novel role of EndophilinAs in sorting of activated BDNF-TrkB receptors into late endosomal compartments. Mice lacking all three EndophilinAs accumulate Rab7-positive late endosomes. Moreover, EndophilinAs are differentially localized to, co-traffic with, and tubulate, distinct endosomal compartments: In response to BDNF, EndophilinA2 is recruited to both early and late endosomes, EndophilinA3 is recruited to Lamp1-positive late endosomes, and co-trafficks with Rab5 and Rab7 in both the presence and absence of BDNF, while EndophilinA1 colocalizes at lower levels with endosomes. The absence of all three EndophilinAs caused TrkB to accumulate in EEA1 and Rab7-positive endosomes, and impaired BDNF-TrkB-dependent survival signaling cascades. In addition, EndophilinA triple knockout neurons exhibited increased cell death which could not be rescued by exogenous BDNF, in a neurotrophin-dependent survival assay. Thus, EndophilinAs differentially regulate activated receptor sorting via distinct endosomal compartments to promote BDNF-dependent cell survival.
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    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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    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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    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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    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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    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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    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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    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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    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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    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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    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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    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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    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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    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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    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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