Journal of Neurochemistry

Cover image for Vol. 130 Issue 3

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Jörg Schulz

Impact Factor: 4.244

ISI Journal Citation Reports © Ranking: 2013: 63/251 (Neurosciences); 74/291 (Biochemistry & Molecular Biology)

Online ISSN: 1471-4159

VIEW

  1. 1 - 66
  1. Short Communications

    1. Elevation of striatal urate in experimental models of Parkinson's disease: a compensatory mechanism triggered by dopaminergic nigrostriatal degeneration?

      Maria Antonietta De Luca, Omar Cauli, Micaela Morelli and Nicola Simola

      Article first published online: 30 JUL 2014 | DOI: 10.1111/jnc.12809

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      This study evaluated the in vivo modifications in the striatal urate levels in the mouse MPTP and the rat 6-OHDA models of Parkinson's disease-like dopaminergic nigrostriatal toxicity. The results obtained demonstrated that dopaminergic neurotoxicity is associated with higher urate levels in the striatum, which would strengthen the idea of a link between endogenous urate and Parkinson's disease.

  2. Original Articles

    1. Amphetamine potency varies with dopamine uptake rate across striatal subregions

      Cody A. Siciliano, Erin S. Calipari and Sara R. Jones

      Article first published online: 30 JUL 2014 | DOI: 10.1111/jnc.12808

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      Amphetamine is a central nervous system psychostimulant with a high potential for abuse, which may be augmented by increased dopamine transporter (DAT) expression. We here show that the ability of amphetamine to inhibit dopamine (DA) transport and deplete dopamine vesicles increases in a graded manner across striatal subregions from ventral to dorsal with the greatest effects on DA neurotransmission in the dorsal caudate-putamen. Additionally, DA uptake rate and amphetamine potency positively correlated, suggesting that differences across regions result from disparate DA transporter levels.

    2. A distinct subfraction of Aβ is responsible for the high-affinity Pittsburgh compound B-binding site in Alzheimer's disease brain

      Sergey V. Matveev, Hans Peter Spielmann, Brittney M. Metts, Jing Chen, Fredrick Onono, Haining Zhu, Stephen W. Scheff, Lary C. Walker and Harry LeVine III

      Article first published online: 27 JUL 2014 | DOI: 10.1111/jnc.12815

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      A lipid-associated subpopulation of Aβ accounts for the high-affinity binding of Pittsburgh compound B (PIB) in Alzheimer's disease brain. Mass spectrometry of the isolated PIB-binding site from frontal cortex identified Aβ peptides and a set of plaque-associated proteins in AD but not age-matched normal brain. The PIB-binding site may represent a particularly pathogenic entity and/or report local pathologic conditions.

    3. Hypoxia-inducible factor-1α mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells

      Hecheng Wang, Miao Sun, Huan Yang, Xiaosheng Tian, Yawei Tong, Ting Zhou, Tao Zhang, Yaoyun Fu, Xiangyang Guo, Dongsheng Fan, Albert Yu, Ming Fan, Xuefei Wu, Weizhong Xiao and Dehua Chui

      Article first published online: 27 JUL 2014 | DOI: 10.1111/jnc.12795

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      HIF-1 binded to and disassociated HDAC-1 from NEP promoter, activating NEP gene expression at early stage of hypoxia. HDAC-1 protein level was elevated at late stage of hypoxia that exceeded the binding capacity of HIF-1 to prevent association of HDAC-1 from NEP promoter, leading to suppression of NEP.

    4. Detergent-dependent separation of postsynaptic density membrane rafts and other subsynaptic structures from the synaptic plasma membrane of rat forebrain

      LiYing Zhao, Hiroyuki Sakagami and Tatsuo Suzuki

      Article first published online: 24 JUL 2014 | DOI: 10.1111/jnc.12807

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      We systematically investigated the purification process of post-synaptic density (PSD) and synaptic membrane rafts by examining the structures obtained after treatment of the SPMs with TX-100, n-octyl β-d-glucoside or CHAPSO. Differential distribution of type I and type II PSD, synaptic membrane rafts, and other novel subdomains in the SPM give clues to understand the structural organization of synapses at the molecular level.

  3. Reviews

    1. You have free access to this content
      Glutamate synthesis has to be matched by its degradation – where do all the carbons go?

      Ursula Sonnewald

      Article first published online: 23 JUL 2014 | DOI: 10.1111/jnc.12812

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      Intermediates leave the tricarboxylic acid cycle and must be replaced by a process termed anaplerosis that must be coupled to cataplerosis. We hypothesize that cataplerosis is achieved by exporting the lactate generated from the cycle into the blood and perivascular area. This shifts the paradigm of lactate generation as solely derived from glycolysis to that of oxidation and might present an alternative explanation for aerobic glycolysis.

  4. Original Articles

    1. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein

      Nicola J. Rutherford, Brenda D. Moore, Todd E. Golde and Benoit I. Giasson

      Article first published online: 21 JUL 2014 | DOI: 10.1111/jnc.12806

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      The α-synuclein (SNCA) mutations, H50Q and G51D, cause Parkinson's disease. We found that H50Q increases and G51D decreases the rate of α-synuclein aggregation in vitro, and cells over-expressing the mutant proteins show decreased viability when stressed, compared to wild type. G51D is the first SNCA mutation to show decreased α-synuclein aggregation, suggesting a distinct disease mechanism to other SNCA mutations.

    2. HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice

      Ruoli L. Chen, Lara O. O. Ogunshola, Karkheng K. Yeoh, Anant Jani, Michalis Papadakis, Simon Nagel, Christopher J. Schofield and Alastair M. Buchan

      Article first published online: 18 JUL 2014 | DOI: 10.1111/jnc.12804

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      We show that IOX3, a selective small molecule (280.66 Da) HIF prolyl hydroxylase inhibitor, could up-regulate HIF-1α and increase erythropoietin expression in mice. We further demonstrate that HIF stabilization with IOX3 before cerebral ischaemia is neuroprotective partially because of blood–brain barrier (BBB) protection, while immediate application is detrimental both in vivo and in vitro. These findings provide new insights into the role of HIF stabilization in ischaemic stroke.

    3. Primary glioblastoma cultures: can profiling of stem cell markers predict radiotherapy sensitivity?

      Dieter Lemke, Markus Weiler, Jonas Blaes, Benedikt Wiestler, Leonie Jestaedt, Ann-Catherine Klein, Sarah Löw, Günter Eisele, Bernhard Radlwimmer, David Capper, Kirsten Schmieder, Michel Mittelbronn, Stephanie E. Combs, Martin Bendszus, Michael Weller, Michael Platten and Wolfgang Wick

      Article first published online: 18 JUL 2014 | DOI: 10.1111/jnc.12802

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      Markers used to define glioma-initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or – resistance, but a SOX-2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity.

    4. Excitatory GABA induces BDNF transcription via CRTC1 and phosphorylated CREB-related pathways in immature cortical cells

      Mamoru Fukuchi, Yuya Kirikoshi, Atsumi Mori, Reika Eda, Daisuke Ihara, Ichiro Takasaki, Akiko Tabuchi and Masaaki Tsuda

      Article first published online: 18 JUL 2014 | DOI: 10.1111/jnc.12801

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      We demonstrated that GABA induced Bdnf expression at the early stage of the culture, in which GABA exerted its excitatory action. The excitatory GABA-induced Bdnf expression was controlled by multiple Ca2+ signaling pathways evoked via L-VDCC. Both the CREB coactivator, CRTC1 and CREB phosphorylation participated in excitatory GABA-induced Bdnf transcription. Our present study indicates the mechanism underlying the excitatory GABA-induced Bdnf expression in immature neurons and provide new insights into molecular mechanisms underlying Bdnf expression to control neuronal development.

  5. Obituary

    1. Marie T. Filbin

      F. Anne Stephenson

      Article first published online: 15 JUL 2014 | DOI: 10.1111/jnc.12797

  6. Original Articles

    1. Differential protein–protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways

      Lauran Reyniers, Maria Grazia Del Giudice, Laura Civiero, Elisa Belluzzi, Evy Lobbestael, Alexandra Beilina, Giorgio Arrigoni, Rita Derua, Etienne Waelkens, Yan Li, Claudia Crosio, Ciro Iaccarino, Mark R. Cookson, Veerle Baekelandt, Elisa Greggio and Jean-Marc Taymans

      Article first published online: 14 JUL 2014 | DOI: 10.1111/jnc.12798

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      LRRK1 and LRRK2 (leucine-rich repeat kinase) interaction partners were identified by two different protein-protein interaction screens. These confirmed epidermal growth factor receptor (EGR-R) as a LRRK1-specific interactor, while 14-3-3 proteins were LRRK2-specific. Functional analysis of these interactions and the pathways they mediate shows that LRRK1 and LRRK2 signaling do not intersect, reflective of the differential role of both LRRKs in Parkinson's disease.

    2. A functional variant in the 5′-flanking region of the chicken serotonin transporter gene is associated with increased body weight and locomotor activity

      Loc Phi-van, Marlis Holtz, Joergen B. Kjaer, Valerie D. van Phi and Katrin Zimmermann

      Article first published online: 10 JUL 2014 | DOI: 10.1111/jnc.12799

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      We identified a polymorphism in the 5´-flanking region of the chicken serotonin transporter (5-HTT) gene. The expression of 5-HTT in D/D chickens was higher than that in W/W and W/D chickens. D/D females showed significant greater increase in body weight from 6 weeks of age, higher body mass index and higher content of intra-abdominal fat. The presence of D/D alleles resulted in increase in physical activity.

    3. SVCT2 transporter expression is post-natally induced in cortical neurons and its function is regulated by its short isoform

      Katterine Salazar, Gustavo Cerda, Fernando Martínez, José M. Sarmiento, Carlos González, Federico Rodríguez, María García-Robles, Juan Carlos Tapia, Manuel Cifuentes and Francisco Nualart

      Article first published online: 10 JUL 2014 | DOI: 10.1111/jnc.12793

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      The sodium–vitamin C cotransporter, SVCT2, is induced in neurons within the inner layer of the brain cortex during post-natal development, mainly in pyramidal cortex neurons. Two different isoforms, SVCT2wt and SVCT2sh, were detected. Using in vitro studies, we suggest a molecular interaction between SVCT2wt and SVCT2sh, which may regulate the affinity of vitamin C uptake.

    4. Ectonucleotide pyrophosphatase/phosphodiesterase activity in Neuro-2a neuroblastoma cells: changes in expression associated with neuronal differentiation

      Rosa Gómez-Villafuertes, Jesús Pintor, María Teresa Miras-Portugal and Javier Gualix

      Article first published online: 10 JUL 2014 | DOI: 10.1111/jnc.12794

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      We described the presence of an ectoenzymatic activity able to hydrolyse diadenosine polyphosphates (ApnA) in N2a cells. This activity displays biochemical features that are typical of the ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) family members, as demonstrated by the use of the fluorogenic compound BODIPY-FL-GTPγS. Both NPP1 and NPP3 ectoenzymes are expressed in N2a cells, their levels dramatically changing when cells differentiate into a neuronal-like phenotype. Activity assays in differentiated cells showed that the ApnA-hydrolytic activity largely depends on the NPP1 isozyme.

    5. Induction of serpinb1a by PACAP or NGF is required for PC12 cells survival after serum withdrawal

      Tommy Seaborn, Aurélia Ravni, Ruby Au, Bill K. C. Chow, Alain Fournier, Olivier Wurtz, Hubert Vaudry, Lee E. Eiden and David Vaudry

      Article first published online: 10 JUL 2014 | DOI: 10.1111/jnc.12780

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      Pituitary adenylate cyclase-activating polypeptide (PACAP) and nerve growth factor (NGF) induce a strong increase in serpinb1 a expression in PC12 cells. Functional investigations revealed that this increase in serpinb1a does not affect cell proliferation or differentiation but inhibits caspase 3 activity and promotes cell survival.

  7. News and ISN

    1. News and ISN

      Article first published online: 9 JUL 2014 | DOI: 10.1111/jnc.12791

  8. Original Articles

    1. Endothelin-1 increases the expression of VEGF-R1/Flt-1 receptors in rat cultured astrocytes through ETB receptors

      Yutaka Koyama, Mio Hayashi, Ryuji Nagae, Shogo Tokuyama and Tomohiro Konishi

      Article first published online: 8 JUL 2014 | DOI: 10.1111/jnc.12770

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      To clarify the regulatory mechanisms of vascular endothelial growth factor (VEGF) receptors, the effects of endothelin-1 (ET-1) were examined in rat cultured astrocytes. Effects of selective VEGF-R1 and R2 agonist showed that these receptors were linked to focal adhesion kinase (FAK) and extracellular signal regulated kinase 1/2 (ERK1/2). Treatment with ET-1 increased expression of VEGF-R1, which was mediated by ETB receptors. Pre-treatment with ET-1 potentiated the VEGF-R1-mediated activations of FAK and ERK1/2. These findings suggest that ET-1 induces up-regulation of VEGF-R1 receptors in astrocytes.

    2. Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression

      Junhui Wang, Jinping Qiao, Yanbo Zhang, Hongxing Wang, Shenghua Zhu, Handi Zhang, Kelly Hartle, Huining Guo, Wei Guo, Jue He, Jiming Kong, Qingjun Huang and Xin-Min Li

      Article first published online: 8 JUL 2014 | DOI: 10.1111/jnc.12792

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      We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.

    3. Putative roles of Ca2+-independent phospholipase A2 in respiratory chain-associated ROS production in brain mitochondria: influence of docosahexaenoic acid and bromoenol lactone

      Caroline Nordmann, Mikhail Strokin, Peter Schönfeld and Georg Reiser

      Article first published online: 8 JUL 2014 | DOI: 10.1111/jnc.12789

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      The Ca2+-independent phospholipase A2 (iPLA2), a FFA (free fatty acids)-generating membrane-attached mitochondrial phospholipase, is potential to regulate ROS (reactive oxygen species) generation by mitochondria. FFA can either decrease reversed electron transport (RET)-linked or enhance forward electron transport (FET)-linked ROS generation. In the physiological mode of FET, iPLA2 activity increases ROS generation. The iPLA2 inhibitor BEL exerts detrimental effects on energy-dependent mitochondrial functions.

  9. Editorial Highlights

    1. You have free access to this content
      Peripheral and cognitive signs: delineating the significance of impaired catecholamine metabolism in Parkinson's disease progression

      Michael F. Salvatore, Elizabeth A. Disbrow and Marina E. Emborg

      Article first published online: 5 JUL 2014 | DOI: 10.1111/jnc.12796

      Read the full articleA vesicular sequestration - to - oxidative deamination shift in myocardial sympathetic nerves in Parkinson disease’ on doi: 10.1111/jnc.12766

  10. Original Articles

    1. S100B protein activates a RAGE-dependent autocrine loop in astrocytes: implications for its role in the propagation of reactive gliosis

      Alejandro Villarreal, Rocío Seoane, Agustina González Torres, Gerardo Rosciszewski, Maria Florencia Angelo, Alicia Rossi, Philip A. Barker and Alberto Javier Ramos

      Article first published online: 5 JUL 2014 | DOI: 10.1111/jnc.12790

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      We propose that S100B turns astrocytes into a reactive phenotype in a RAGE-dependent manner but engaging different intracellular pathways. While both nanomolar and micromolar S100B turn astrocytes into a reactive phenotype, micromolar S100B induces a conversion into a pro-inflammatory-neurodegenerative profile that facilitates neuronal death of OGD-exposed neurons. We think that S100B/RAGE interaction is essential to expand reactive gliosis in the injured brain being a tempting target for limiting reactive gliosis to prevent the glial conversion into the neurodegenerative profile.

    2. Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury

      Binnur Eroglu, Donald E. Kimbler, Junfeng Pang, Justin Choi, Demetrius Moskophidis, Nathan Yanasak, Krishnan M. Dhandapani and Nahid F. Mivechi

      Article first published online: 4 JUL 2014 | DOI: 10.1111/jnc.12781

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      Our data indicate that loss of Hsp110 or Hsp70 in mice increases brain injury following TBI. (a) One of the mechanisms underlying the increased cell death observed in the absence of these Hsps following TBI is the increased expression of ROS-induced p53 target genes known as Pigs. In addition, (b) using drugs (Celastrol or BGP-15) to increase Hsp70/Hsp110 levels protect cells against TBI, suggesting the beneficial effects of Hsp70/Hsp110 inducers to reduce the pathological consequences of TBI.

    3. Functional characterization of the S41Y (C2755A) polymorphism of tryptophan hydroxylase 2

      Nurgul Carkaci-Salli, Ugur Salli, Izel Tekin, Jeremy A. Hengst, Moe K. Zhao, T. Lee Gilman, Anne M. Andrews and Kent E. Vrana

      Article first published online: 28 JUN 2014 | DOI: 10.1111/jnc.12779

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      We report the functional implications of a polymorphic human tryptophan hydroxylase-2 gene associated with depression and bipolar disorder. The polymorphic enzyme (serine-41 converted to tyrosine) has increased activity, but decreased enzyme stability and serotonin production. Moreover, cyclic AMP-dependent protein kinase (PKA)-mediated phosphorylation of the mutant enzyme is decreased suggesting modified regulation of the S41Y variant leading to altered serotonin.

  11. Editorial Highlights

    1. You have free access to this content
      Motor learning and long-term plasticity of parallel fibre-Purkinje cell synapses require post-synaptic Cdk5/p35

      Elek Molnár

      Article first published online: 27 JUN 2014 | DOI: 10.1111/jnc.12788

      Read the full articleCdk5/p35 is required for motor coordination and cerebellar plasticity’ on doi: 10.1111/jnc.12756.

  12. Original Articles

    1. Neuroprotective effect of exercise in rat hippocampal slices submitted to in vitro ischemia is promoted by decrease of glutamate release and pro-apoptotic markers

      Flávio Afonso Gonçalves Mourão, Hércules Ribeiro Leite, Luciana Estefani Drumond de Carvalho, Talita Hélen Ferreira e Vieira, Mauro Cunha Xavier Pinto, Daniel de Castro Medeiros, Ian Lara Lamounier Andrade, Daniela Fontes Gonçalves, Grace Schenatto Pereira, Márcio Flávio Dutra Moraes and André Ricardo Massensini

      Article first published online: 27 JUN 2014 | DOI: 10.1111/jnc.12786

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      Exercise reduces excitotoxicity and apoptosis. The mechanisms underlying neuroprotective effects of regular exercise are still not fully understood. Here, we showed that swim training promotes neuroprotection decreasing pro-apoptotic markers as caspases 8, 9, 3, and apoptose-Inducing Factor (AIF) as well as glutamate release from hippocampal slices. Our data reinforce the idea that exercise affords a neuroprotective effect.

    2. Tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 constitutively interacts with ankyrin G

      Audrey Montersino, Anna Brachet, Géraldine Ferracci, Marie-Pierre Fache, Stephanie Angles d'Ortoli, Wenjing Liu, Fanny Rueda-Boroni, Francis Castets and Bénédicte Dargent

      Article first published online: 27 JUN 2014 | DOI: 10.1111/jnc.12785

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      The peripheral voltage-gated sodium channel Nav1.8 can be abnormally expressed in central nervous system (CNS) neurons in cases of neuronal injury. We here demonstrated that Nav1.8 binds strongly and constitutively to the scaffolding protein ankyrin G. This indicates that Nav1.8 concentrates at the ankyrin G micro-domains and could disturb the electrophysiological signature of CNS neurons where it is ectopicaly expressed.

    3. The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1β and TNF-α expression in rat hippocampus

      Carlos D. Gómez, Rudolf M. Buijs and María Sitges

      Article first published online: 27 JUN 2014 | DOI: 10.1111/jnc.12784

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      The mechanism of action of anti-seizure drugs like vinpocetine and carbamazepine involves a decrease in Na+ channels permeability. We here propose that this mechanism of action also involves a decrease in cerebral inflammation.

    4. Hippocampal proteoglycans brevican and versican are linked to spatial memory of Sprague–Dawley rats in the morris water maze

      Sivaprakasam R. Saroja, Ajinkya Sase, Susanne G. Kircher, Jia Wan, Johannes Berger, Harald Höger, Arnold Pollak and Gert Lubec

      Article first published online: 27 JUN 2014 | DOI: 10.1111/jnc.12783

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      Proteoglycans (PGs) are major constituents of the extracellular matrix of the brain and were proposed to contribute to synaptic plasticity. This report addressed PGs in rat hippocampus and suggests that PGs brevican and versican are linked to spatial memory, and form a complex with the GluR1 subunit of the AMPA receptor, a key signaling molecule in memory mechanisms.

    5. Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression

      Jeffrey L. Barr, Gina L. Forster and Ellen M. Unterwald

      Article first published online: 23 JUN 2014 | DOI: 10.1111/jnc.12764

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      A behaviorally sensitizing regimen of cocaine (20 mg/kg, ip 7 days) also sensitized ventral hippocampus (hipp)-mediated dopaminergic transmission within the nucleus accumbens (Nac) to NMDA stimulation (bolts). This was associated with reduced ventral hippocampal NR2A:NR2B subunit ratio, suggesting that repeated exposure to cocaine produces changes in hippocampal NMDA receptor composition that lead to enhanced ventral hippocampus–nucleus accumbens communication.

    6. The design and delivery of a PKA inhibitory polypeptide to treat SCA1

      Scoty M. Hearst, Qingmei Shao, Mariper Lopez, Drazen Raucher and Parminder J. S. Vig

      Article first published online: 23 JUN 2014 | DOI: 10.1111/jnc.12782

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      Protein kinase A (PKA) phosphorylates mutant ataxin-1 and makes it resistant to degradation. We designed a PKA inhibitory polypeptide. Our polypeptide comprised a thermally responsive elastin-like peptide (ELP) carrier, a PKA inhibitory peptide (PKI) and a cell-penetrating peptide (Synb1). Synb1-ELP-PKI, inhibited PKA activity in various in vitro models. The polypeptide crossed the blood–brain barrier when administered intraperitoneally or intranasally. We demonstrate that our polypeptide is a potential candidate for Spinocerebellar ataxia-1 (SCA1) therapy.

    7. Dynamics of hippocampal acetylcholine release during lithium-pilocarpine-induced status epilepticus in rats

      Markus H. Hillert, Imran Imran, Martina Zimmermann, Helene Lau, Stefanie Weinfurter and Jochen Klein

      Article first published online: 22 JUN 2014 | DOI: 10.1111/jnc.12787

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      Status epilepticus was induced in rats by lithium-pilocarpine administration, and extracellular levels of acetylcholine (ACh) were measured in the hippocampus by microdialysis. Seizures caused several-fold increases of ACh levels which were reduced to control levels when seizures were stopped by diazepam or ketamine. Further experiments confirmed that cholinergic hyperexcitation accompanies status epilepticus, even when kainate was used as inducing agent.

    8. The high-affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

      Mrudang Shah, Subramanian Rajagopalan, Liping Xu, Chandrashekhar Voshavar, Yevgeniya Shurubor, Flint Beal, Julie K. Andersen and Aloke K. Dutta

      Article first published online: 21 JUN 2014 | DOI: 10.1111/jnc.12767

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      Neuroprotective properties of dopamine D2/D3 agonist D-512 was evaluated both in vitro and in vivo models of Parkinson's disease (PD). D-512 rescued PC12 cells from toxicity induced by 6-hydroxydopamine (6-OHDA). D-512 reduced intracellular reactive oxygen species and lipid peroxidation as well as protection of DNA damage from toxicity of 6-OHDA. D-512 was protective against neurodegenerative phenotypes induced by MPTP in mouse. Our studies strongly suggest that D-512 with its multifunctional property may constitute a novel viable therapy for Parkinson's disease.

    9. Use of cysteine-reactive cross-linkers to probe conformational flexibility of human DJ-1 demonstrates that Glu18 mutations are dimers

      Janani Prahlad, David N. Hauser, Nicole M. Milkovic, Mark R. Cookson and Mark A. Wilson

      Article first published online: 19 JUN 2014 | DOI: 10.1111/jnc.12763

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      DJ-1 is a homodimeric protein that protects cells against oxidative stress. Designed mutations that influence the regulatory oxidation of a key cysteine residue have recently been proposed to disrupt DJ-1 dimerization. We use cysteine cross-linking and various biophysical techniques to show that these DJ-1 mutants form dimers with increased conformational flexibility.

    10. Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease-associated ubiquitin C-terminal hydrolase L1 and alters its structure and function

      Viorica Raluca Contu, Yaichiro Kotake, Takashi Toyama, Katsuhiro Okuda, Masatsugu Miyara, Shuichiro Sakamoto, Shigeyoshi Samizo, Seigo Sanoh, Yoshito Kumagai and Shigeru Ohta

      Article first published online: 18 JUN 2014 | DOI: 10.1111/jnc.12762

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      We investigated the interaction between ubiquitin C-terminal hydrolase L1 (UCH-L1) and the brain endogenous parkinsonism inducer 1-(3′,4′-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3′,4′DHBnTIQ). Our results indicate that 3′,4′DHBnTIQ binds to UCH-L1 specifically at cysteine 152 and induces its aggregation. 3′,4′DHBnTIQ also inhibits the hydrolase activity of UCH-L1. Catechol-modified as well as insoluble UCH-L1 were detected in the midbrains of MPTP-treated Parkinson's disease (PD) model mice. Conjugation of UCH-L1 by neurotoxic endogenous compounds like 3′,4′DHBnTIQ might play a key role in onset and progression of PD.

    11. Functional analysis and purification of a Pen-2 fusion protein for γ-secretase structural studies

      Oliver Holmes, Swetha Paturi, Michael S. Wolfe and Dennis J. Selkoe

      Article first published online: 18 JUN 2014 | DOI: 10.1111/jnc.12772

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      We present a method by which an MBP-tagged form of the Pen-2 subunit of γ-secretase may be purified from bacteria to mg quantities at greater than 95% purity. We show that this construct is incorporated into and allows full activity of γ-secretase in a mammalian system. These methods provide valuable tools to study the structure and function of Pen-2 and γ-secretase.

    12. Astrocyte-dependent protective effect of quetiapine on GABAergic neuron is associated with the prevention of anxiety-like behaviors in aging mice after long-term treatment

      Junhui Wang, Shenghua Zhu, Hongxing Wang, Jue He, Yanbo Zhang, Abulimiti Adilijiang, Handi Zhang, Kelly Hartle, Huining Guo, Jiming Kong, Qingjun Huang and Xin-Min Li

      Article first published online: 18 JUN 2014 | DOI: 10.1111/jnc.12771

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      The neuroprotective properties of quetiapine (QTP) have not been fully understood. Here, we identify a novel mechanism by which QTP increases the synthesis of ATP in astrocytes and protects GABAergic neurons from aging-induced death in a primary cell culture model. In 12-month-old mice, QTP significantly improves cell number of GABAegic neurons and ameliorates anxiety-like behaviors. Our study indicates that astrocytes may be the conduit through which QTP exerts its neuroprotective effects on GABAergic neurons.

    13. Ionizing radiation causes increased tau phosphorylation in primary neurons

      Li Li, Wenzhang Wang, Scott Welford, Teng Zhang, Xinglong Wang and Xiongwei Zhu

      Article first published online: 16 JUN 2014 | DOI: 10.1111/jnc.12769

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      Alzheimer disease is considered as a significant radiation late effect. In this study, we investigated whether ionizing radiation causes changes in tau phosphorylation and found that γ rays cause increased tau phosphorylation at multiple sites in a dose and time-dependent manner in primary neurons which are mediated by oxidative stress-dependent activation of JNK and ERK. Oxidative stress-independent activation of GSK3β is also involved. Overall, our studies suggest that ionizing radiation may cause increased risk for Alzheimer disease development by promoting abnormal tau phosphorylation.

    14. Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation

      Dan-Ju Luo, Qiong Feng, Zhi-Hao Wang, Dong-Sheng Sun, Qun Wang, Jian-Zhi Wang and Gong-Ping Liu

      Article first published online: 16 JUN 2014 | DOI: 10.1111/jnc.12761

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      Phosphotyrosyl phosphatase activator (PTPA) is decreased in the brains of Alzheimer's disease (AD) and AD transgenic mouse models. Here, we investigated whether down-regulation of PTPA affects cell viability. We found that PTPA located in the integral membrane of mitochondria, and knockdown of PTPA induced cell apoptosis in HEK293 and N2a cell lines by decreasing mitochondrial membrane potential, which leads to translocation of Bax and a simultaneous release of Cyt C. In the cells with tau over-expression, PTPA knockdown inactivated PP2A to phosphorylate tau to avoid cell apoptosis which induced by PTPA knockdown.

    15. You have full text access to this OnlineOpen article
      Neuronal influences are necessary to produce mitochondrial co-localization with glutamate transporters in astrocytes

      Christopher I. Ugbode, Warren D. Hirst and Marcus Rattray

      Article first published online: 16 JUN 2014 | DOI: 10.1111/jnc.12759

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      Mitochondria have limited co-localization with the glutamate transporter GLT-1 in primary astrocytes in culture. Few mitochondria are in the fine processes where GLT-1 is abundant. It is necessary to culture astrocytes with neurones to drive a significant level of co-localization, but co-localization is not further altered by depolarization, manipulating sodium ion gradients or Na/K ATPase activity.

    16. Destabilization of survival factor MEF2D mRNA by neurotoxin in models of Parkinson's disease

      Bao Wang, Zhibiao Cai, Fangfang Lu, Chen Li, Xiaofei Zhu, Linna Su, Guodong Gao and Qian Yang

      Article first published online: 16 JUN 2014 | DOI: 10.1111/jnc.12765

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      Myocyte enhancer factor 2D (MEF2D) plays an important role in neuronal survival. How MEF2D mRNA is deregulated under toxic stress is unclear. We found that PD-associated neurotoxins destabilize MEF2D mRNA and reduce its level in vitro and in vivo. Reduction in MEF2D mRNA is sufficient to sensitize model cells to neurotoxin-induced toxicity, suggesting that destabilization of MEF2D mRNA is part of the mechanism by which neurotoxins trigger deregulation of neuronal survival.

    17. A vesicular sequestration to oxidative deamination shift in myocardial sympathetic nerves in Parkinson's disease

      David S. Goldstein, Patricia Sullivan, Courtney Holmes, Gary W. Miller, Yehonatan Sharabi and Irwin J. Kopin

      Article first published online: 13 JUN 2014 | DOI: 10.1111/jnc.12766

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      We found that the majority (70%) of Parkinson's disease (PD) patients have profound (98%) myocardial norepinephrine depletion, because of both cardiac sympathetic denervation and a shift from vesicular sequestration to oxidative deamination of cytoplasmic catecholamines in the residual nerves. This shift may be part of a final common pathogenetic pathway in the loss of catecholaminergic neurons that characterizes PD.

    18. GM1 ganglioside enhances Ret signaling in striatum

      Erin N. Newburn, Anne-Marie Duchemin, Norton H. Neff and Maria Hadjiconstantinou

      Article first published online: 13 JUN 2014 | DOI: 10.1111/jnc.12760

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      It has been proposed that the ganglioside GM1 promotes neuronal growth, phenotypic expression, and survival by modulating tyrosine kinase receptors for neurotrophic factors. We provide evidence that the GM1 enhances the activity of Ret tyrosine kinase receptor for glia cell-derived neurotrophic factor (GDNF) in the striatum in situ and in vivo, and propose that this might be a mechanism for GM1's neurotrophic actions on dopaminergic neurons. Ret activation is followed by Tyr1062 and Tyr981 phosphorylation and recruitment of PI3-K/Akt, Erk, and Src signaling. GM1 apparently acts by increasing the binding of endogenous GDNF to GFRα1 co-receptor, which is required for the GM1 effect on Ret.

    19. Mu-opioid receptor splice variants: sex-dependent regulation by chronic morphine

      Vittorio Verzillo, Priyanka A. Madia, Nai-Jiang Liu, Sumita Chakrabarti and Alan R. Gintzler

      Article first published online: 11 JUN 2014 | DOI: 10.1111/jnc.12768

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      Chronic systemic morphine increases levels of mRNA encoding two splice variants of mu-opioid receptor (MOR), MOR-1B2 and MOR-1C1, variants differing from rMOR-1 in their C-terminal (and phosphorylation sites therein) and thus possibly signaling sequelae. This adaptation is sex-specific. It occurs in the spinal cord of males, but not females, indicating the importance of sex-specific mechanisms for and treatments of tolerance and addiction.

  13. Editorial Highlights

    1. You have free access to this content
      GFAP variants in health and disease: stars of the brain… and gut

      Susan M. Sullivan

      Article first published online: 9 JUN 2014 | DOI: 10.1111/jnc.12754

      Read the full article ‘Enteric GFAP expression and phosphorylation in Parkinson's disease’ on doi: 10.1111/jnc.12742.

  14. Reviews

    1. You have free access to this content
      Dyskinesia in Parkinson's disease: mechanisms and current non-pharmacological interventions

      Rolf Heumann, Rosario Moratalla, Maria Trinidad Herrero, Koushik Chakrabarty, René Drucker-Colín, Jose Ruben Garcia-Montes, Nicola Simola and Micaela Morelli

      Article first published online: 7 JUN 2014 | DOI: 10.1111/jnc.12751

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      This review aims at summarizing the key molecular mechanisms underlying dyskinesia and the most recent therapeutic advances to treat Parkinson's disease with emphasis on non-pharmacological interventions such as physical activity, deep brain stimulation (DBS), transcranial magnetic field stimulation (TMS) and cell replacement therapy. These new interventions are discussed from both the experimental and clinical point of view, describing their current strength and limitations.

  15. Original Articles

    1. Enteric GFAP expression and phosphorylation in Parkinson's disease

      Thomas Clairembault, Willem Kamphuis, Laurène Leclair-Visonneau, Malvyne Rolli-Derkinderen, Emmanuel Coron, Michel Neunlist, Elly M. Hol and Pascal Derkinderen

      Article first published online: 6 JUN 2014 | DOI: 10.1111/jnc.12742

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      We showed that GFAP is over-expressed and hypophosphorylated in the enteric glial cells (EGCs) of Parkinson's disease (PD) patients as compared to healthy subjects and patients with atypical parkinsonism (MSA, multiple system atrophy and PSP, progressive supranuclear palsy). Our findings provide evidence that enteric glial reaction occurs in PD but not in PSP and MSA and further reinforce the role of the enteric nervous system in the pathophysiology of PD.

    2. Pre-treatment with the synthetic antioxidant T-butyl bisphenol protects cerebral tissues from experimental ischemia reperfusion injury

      Thi Thuy Hong Duong, Belal Chami, Aisling C. McMahon, Genevieve M. Fong, Joanne M. Dennis, Saul B. Freedman and Paul K. Witting

      Article first published online: 6 JUN 2014 | DOI: 10.1111/jnc.12747

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      We demonstrate that pre-treatment with ditert-butyl bisphenol(Di-t-Bu-BP) inhibits lipid, protein, and total thiol oxidation and decreases caspase activation and infarct size in rats subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. These data suggest that inhibition of oxidative stress contributes significantly to neuroprotection.

    3. Inhibition of PaCaMKII-E isoform in the dorsal unpaired median neurosecretory cells of cockroach reduces nicotine- and clothianidin-induced currents

      Olivier List, Delphine Calas-List, Emiliane Taillebois, Marjorie Juchaux, Emilie Heuland and Steeve H. Thany

      Article first published online: 28 MAY 2014 | DOI: 10.1111/jnc.12752

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      Cellular responses to Ca2+ require intermediary proteins such as calcium/calmodulin-dependent protein kinase II (CaMKII). We recently demonstrated that the cockroach genome encodes five different CaMKII isoforms and only PaCaMKII-E isoform was specifically expressed in the dorsal unpaired median neurosecretory cells. Here we show that specific inhibition of PaCaMKII-E isoform is associated with a decrease in nicotine- and clothianidin-induced currents. In addition, analysis of calcium changes demonstrates that PaCaMKII-E inhibition induces a decrease in intracellular calcium concentration.

    4. Regulation of peroxisome proliferator-activated receptor β/δ expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astrocytes

      Dmitry V. Chistyakov, Stepan Aleshin, Marina G. Sergeeva and Georg Reiser

      Article first published online: 28 MAY 2014 | DOI: 10.1111/jnc.12757

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      Protein expression level of nuclear receptor PPARβ/δ is important for functions of this transcription factor. We investigate the regulatory mechanisms of PPARβ/δ in rat primary astrocytes stimulated by agonists of toll-like receptors (TLR): TLR4, TLR1/2, and TLR5. Expression, activity, mRNA stability, and superinduction of PPARβ/δ were up-regulated after TLR stimulation. These processes are sensitive to MAPKs and NF-kB inhibitors. Superinduction is up-regulation of mRNA expression after inhibition of protein synthesis.

    5. Cdk5/p35 is required for motor coordination and cerebellar plasticity

      Xiaojuan He, Masato Ishizeki, Naoki Mita, Seitaro Wada, Yoshifumi Araki, Hiroo Ogura, Manabu Abe, Maya Yamazaki, Kenji Sakimura, Katsuhiko Mikoshiba, Takafumi Inoue and Toshio Ohshima

      Article first published online: 28 MAY 2014 | DOI: 10.1111/jnc.12756

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      Purkinje cells play an important role in motor learning, the underlying mechanisms of which have been studied during the last two decades. We report here that the ablation of Cdk5/p35 in Purkinje cells impairs motor coordination, along with deficits in the cerebellar synaptic plasticity, which gives new insights into the mechanism of synaptic plasticity in Purkinje cells.

    6. Neuroactive steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients

      Donatella Caruso, Marta Melis, Giuseppe Fenu, Silvia Giatti, Simone Romano, Maria Grimoldi, Donatella Crippa, Maria Giovanna Marrosu, Guido Cavaletti and Roberto Cosimo Melcangi

      Article first published online: 28 MAY 2014 | DOI: 10.1111/jnc.12745

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      We here demonstrated that, the cerebrospinal fluid and plasma levels of several neuroactive steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis.

    7. You have full text access to this OnlineOpen article
      Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates

      Sigrun Lange, Eridan Rocha-Ferreira, Laura Thei, Priyanka Mawjee, Kate Bennett, Paul R. Thompson, Venkataraman Subramanian, Anthony P. Nicholas, Donald Peebles, Mariya Hristova and Gennadij Raivich

      Article first published online: 24 MAY 2014 | DOI: 10.1111/jnc.12744

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      Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up-regulation of TNFα, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage.

    8. Induction of depressive-like effects by subchronic exposure to cocaine or heroin in laboratory rats

      Noga Zilkha, Eugene Feigin, Noam Barnea-Ygael and Abraham Zangen

      Article first published online: 24 MAY 2014 | DOI: 10.1111/jnc.12753

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      In the present study, we examined the long-term effects of limited subchronic drug exposure on depressive-like symptoms. Our results demonstrate that short-term, subchronic administration of either cocaine or heroin promotes some depressive-like behaviors, while inducing alterations in BDNF protein levels similar to alterations observed in several animal models of depression. In addition, subchronic cocaine or heroin enhanced the anhedonic effect of chronic stress.

    9. Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension

      Judith Pachuau, De-Pei Li, Shao-Rui Chen, Hae-Ahm Lee and Hui-Lin Pan

      Article first published online: 24 MAY 2014 | DOI: 10.1111/jnc.12758

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      Small conductance calcium-activated K+ (SK) channels, calmodulin, and protein kinase CK2 form a molecular complex and regulate neuronal excitability. Our study suggests that augmented CK2 activity in hypertension can increase calmodulin (CaM) phosphorylation, which leads to diminished SK channel function in pre-sympathetic neurons. Diminished SK channel activity plays a role in hyperactivity of pre-sympathetic neurons in the hypothalamus in hypertension.

    10. Heat shock protein 70 induction by valproic acid delays photoreceptor cell death by N-methyl-N-nitrosourea in mice

      Yoshiki Koriyama, Kayo Sugitani, Kazuhiro Ogai and Satoru Kato

      Article first published online: 22 MAY 2014 | DOI: 10.1111/jnc.12750

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      Retinal degenerative diseases are characterized by the loss of photoreceptor cells. We proposed the following cascade for N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell death: MNU gives rise to cleavage of heat shock protein 70 (HSP70); HSP70 induction by valproic acid (VPA) is dually effective against MNU-induced photoreceptor cell loss because of its anti-apoptotic actions and its ability to prevent HSP70 degradation. We hope that the present study heralds a new era in developing therapeutic tools against retinal degenerative diseases.

    11. S100β as an early biomarker of excitotoxic damage in spinal cord organotypic cultures

      Graciela L. Mazzone and Andrea Nistri

      Article first published online: 19 MAY 2014 | DOI: 10.1111/jnc.12748

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      Excitotoxicity is a major mechanism responsible for neuronal death following acute spinal cord injury. The calcium-binding protein S100β is released by astrocytes into the extracellular compartment during the first 24 h after the initial insult and represents a useful biomarker of lesion progression as its level is related to the occurrence and severity of neuronal loss.

    12. Amphetamine-induced release of dopamine in primate prefrontal cortex and striatum: striking differences in magnitude and timecourse

      Hank P. Jedema, Rajesh Narendran and Charles W. Bradberry

      Article first published online: 19 MAY 2014 | DOI: 10.1111/jnc.12743

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      Using microdialysis probes implanted in the cortex and caudate region of non-human primate brains, we observed in vivo differences in the magnitude and temporal profile of extracellular dopamine levels in response to intravenous amphetamine administration.

    13. Rufy3, a protein specifically expressed in neurons, interacts with actin-bundling protein Fascin to control the growth of axons

      Zhe Wei, Ming Sun, Xinyi Liu, Jian Zhang and Ying Jin

      Article first published online: 19 MAY 2014 | DOI: 10.1111/jnc.12740

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      We propose that Rufy3 may control mouse neuron axon development through its specific interaction with Fascin and Drebrin. Over-expression of Rufy3 (Rufy3 OE) leads to longer axons and expands the distribution of Drebrin to almost the entire growth cone. In contrast, knockdown of Rufy3 (Rufy3 RNAi) results in shortened axons and enhanced the percentage of mutipolar neurons. Moreover, silencing of Rufy3 reduces and restricts the expression of Fascin and F-actin to the edge of the growth cone. These findings provide new insights into the molecular regulation of axonal outgrowth and cell polarization in neurons.

    14. The effect of Cyclin-dependent kinase 5 on voltage-dependent calcium channels in PC12 cells varies according to channel type and cell differentiation state

      Kotaro Furusawa, Akiko Asada, Taro Saito and Shin-ichi Hisanaga

      Article first published online: 19 MAY 2014 | DOI: 10.1111/jnc.12746

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      Calcium (Ca2+) influx through voltage-dependent Ca2+ channels (VDCCs) triggers neurotransmitter release from pre-synaptic terminal of neurons. The channel activity of VDCCs is regulated by Cdk5-p35, a neuronal Ser/Thr kinase. However, there have been debates about the regulation of VDCCs by Cdk5. Using PC12 cells, we show that Cdk5-p35 regulates VDCCs in a type (L, P/Q, and N) and differentiation-dependent manner. NGF = nerve growth factor.

    15. OASIS regulates chondroitin 6-O-sulfotransferase 1 gene transcription in the injured adult mouse cerebral cortex

      Hiroaki Okuda, Kouko Tatsumi, Noriko Horii-Hayashi, Shoko Morita, Aya Okuda-Yamamoto, Kazunori Imaizumi and Akio Wanaka

      Article first published online: 6 MAY 2014 | DOI: 10.1111/jnc.12736

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      OASIS, an ER stress-responsive CREB/ATF family member, is up-regulated in the reactive astrocytes of the injured brain. We found that the up-regulated OASIS is involved in the transcriptional regulation of C6ST1 gene, which promotes chondroitin sulfate proteoglycan (CSPG) sulfation. We conclude that OASIS functions as an anti-regenerative transcription factor by establishing a non-permissive microenvironment to regenerating axons.

  16. Editorial Highlights

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      Dynamic plasticity of NMDA receptor-mediated calcium entry in neurons exposed to HIV-tat

      Gabriela K. Popescu

      Article first published online: 30 APR 2014 | DOI: 10.1111/jnc.12737

      Read the full articleHIV-1 protein tat produces biphasic changes in NMDA-evoked increases in intracellular Ca2+ concentration via activation of Src kinase and nitric oxide signaling pathways’ on doi: 10.1111/jnc.12724

  17. Original Articles

    1. Bidirectional interactions between NOX2-type NADPH oxidase and the F-actin cytoskeleton in neuronal growth cones

      Vidhya Munnamalai, Cory J. Weaver, Corinne E. Weisheit, Prahatha Venkatraman, Zeynep Sena Agim, Mark T. Quinn and Daniel M. Suter

      Article first published online: 25 APR 2014 | DOI: 10.1111/jnc.12734

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      We have previously shown that reactive oxygen species (ROS) are critical for actin organization and dynamics in neuronal growth cones as well as neurite outgrowth. Here, we report that the cytosolic subunit p40phox of the NOX2-type NADPH oxidase complex is partially associated with F-actin in neuronal growth cones, while ROS produced by this complex regulates F-actin dynamics and neurite growth. These findings provide evidence for a bidirectional relationship between NADPH oxidase activity and the actin cytoskeleton in neuronal growth cones.

  18. Editorial Highlights

    1. You have free access to this content
      Novel role of glial syntaxin-1B in supporting neuronal survival

      Seungmee Park, Na-Ryum Bin and Shuzo Sugita

      Article first published online: 22 APR 2014 | DOI: 10.1111/jnc.12723

      Read the full article ‘HPC-1/syntaxin 1A and syntaxin 1B play distinct roles in neuronal survival’ on doi: 10.1111/jnc.12722

  19. Original Articles

    1. HIV-1 protein Tat produces biphasic changes in NMDA-evoked increases in intracellular Ca2+ concentration via activation of Src kinase and nitric oxide signaling pathways

      Kelly A. Krogh, Nicole Wydeven, Kevin Wickman and Stanley A. Thayer

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12724

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      HIV-associated neurocognitive disorders (HAND) afflict about half of HIV-infected patients. HIV-infected cells shed viral proteins, such as the transactivator of transcription (Tat), which can cause neurotoxicity by over activation of NMDA receptors (NMDARs). We show that HIV-1 Tat evoked biphasic changes in NMDA-evoked [Ca2+]i responses. Initially, Tat potentiated NMDA-evoked responses following LRP-mediated activation of Src kinase. Subsequently, Tat-induced NMDAR potentiation adapted by activation of a NOS/sGC/PKG pathway that attenuated NMDA-evoked increases in [Ca2+]i. Adaptation may be a novel neuroprotective mechanism to prevent excessive Ca2+ influx. Solid and dashed arrows represent direct and potentially indirect connections, respectively.

    2. HPC-1/syntaxin 1A and syntaxin 1B play distinct roles in neuronal survival

      Takefumi Kofuji, Tomonori Fujiwara, Masumi Sanada, Tatsuya Mishima and Kimio Akagawa

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12722

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      Syntaxin 1A (STX1A) and syntaxin 1B (STX1B) are thought to have similar functions as SNARE proteins. However, we found that STX1A and STX1B play distinct roles in neuronal survival using STX1A−/− mice and STX1B−/− mice. STX1B was important for neuronal survival, possibly by regulating the secretion of neurotrophic factors, such as BDNF, from glial cells.

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