Journal of Neurochemistry

Cover image for Vol. 136 Issue 4

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

Edited By: Jörg Schulz

Impact Factor: 4.281

ISI Journal Citation Reports © Ranking: 2014: 56/252 (Neurosciences); 72/290 (Biochemistry & Molecular Biology)

Online ISSN: 1471-4159


  1. 1 - 47
  1. Original Articles

    1. Conventional protein kinase Cβ-mediated phosphorylation inhibits collapsin response-mediated protein 2 proteolysis and alleviates ischemic injury in cultured cortical neurons and ischemic stroke-induced mice

      Xuan Yang, Xinxin Zhang, Yun Li, Song Han, David W. Howells, Shujuan Li and Junfa Li

      Article first published online: 11 FEB 2016 | DOI: 10.1111/jnc.13538

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      Focal cerebral ischemia induces a large flux of Ca2+ to activate calpain which cleaves collapsin response mediator (CRMP) 2 into breakdown product (BDP). Inhibition of CRMP2 cleavage by calpeptin and TAT-CRMP2 alleviates ischemic injury. Conventional protein kinase C (cPKC)β-mediated phosphorylation could inhibit CRMP2 proteolysis and alleviate ischemic injury in cultured cortical neurons and ischemic stroke-induced mice.

    2. Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's disease

      Arun Kumar Somavarapu and Kasper P. Kepp

      Article first published online: 11 FEB 2016 | DOI: 10.1111/jnc.13535

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      Close to 200 mutations in presenilin 1 (PSEN1) cause Alzheimer's disease, but the biochemical relating these to disease remains debated. The chemical properties of PSEN1 variants were computed and correlated against clinical age of symptom onset. Loss of stability and hydrophobicity and gain of polarity relate to disease onset, suggesting that mutants impair the membrane structure of PSEN1 and that therapies should increase PSEN1 structural integrity.

  2. Reviews

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      Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models

      Shabab B. Hannan, Nina M. Dräger, Tobias M. Rasse, Aaron Voigt and Thomas R. Jahn

      Article first published online: 11 FEB 2016 | DOI: 10.1111/jnc.13532

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      In this review, we combined and summarized several large-scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements.

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      Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology

      Trevor Tyson, Jennifer A. Steiner and Patrik Brundin

      Article first published online: 10 FEB 2016 | DOI: 10.1111/jnc.13449

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      The prion-like hypothesis of α-synuclein pathology suggests a method for the transmission of misfolded α-synuclein from one neuron to another. This hypothesis postulates that misfolded α-synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of α-synuclein and how these may contribute to the prion-like propagation of α-synuclein pathology.

      This article is part of a special issue on Parkinson disease.

  3. Systematic Reviews

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      Parkinson's disease: acid-glucocerebrosidase activity and alpha-synuclein clearance

      Judith Blanz and Paul Saftig

      Article first published online: 10 FEB 2016 | DOI: 10.1111/jnc.13517

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      Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the lysosomal hydrolase β-glucocerebrosidase (GBA1) are a major risk factor for the development of PD and the molecular events linked to the reduced activity of GBA1 and the pathological accumulation of lipids and α-synuclein are just at the beginning to be understood. New therapeutic concepts in regards to how to increase the expression, stability, or delivery of β-glucocerebrosidase to lysosomes are currently developed.

      This article is part of a special issue on Parkinson disease.

  4. Reviews

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      Therapeutic approaches in Parkinson's disease and related disorders

      Elvira Valera and Eliezer Masliah

      Article first published online: 10 FEB 2016 | DOI: 10.1111/jnc.13529

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      Synucleinopathies, neurodegenerative disorders characterized by the abnormal accumulation of the protein alpha-synuclein, constitute the second leading cause of parkinsonism and dementia in the elderly population, however, no disease-modifying options are available yet. In this review, we summarize the therapeutic approaches currently being explored for synucleinopathies, suggest possible explanations to the clinical outcomes, and propose areas of further therapeutic improvement.

      This article is part of a special issue on Parkinson disease.

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      Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics

      Abdel A. Belaidi and Ashley I. Bush

      Article first published online: 10 FEB 2016 | DOI: 10.1111/jnc.13425

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      Iron plays a fundamental role in maintaining the high metabolic and energetic requirements of the brain. However, iron has to be maintained in a delicate balance as both iron overload and iron deficiency are detrimental to the brain and can trigger neurodegeneration. Here, we discuss the current knowledge on brain iron homeostasis and its involvement in major aging-related neurodegenerative diseases.

      This article is part of a special issue on Parkinson disease.

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      Biological confounders for the values of cerebrospinal fluid proteins in Parkinson's disease and related disorders

      Brit Mollenhauer, Lucilla Parnetti, Irena Rektorova, Milica G. Kramberger, Maria Pikkarainen, Walter J. Schulz-Schaeffer, Dag Aarsland, Per Svenningsson, Lucia Farotti, Marcel M. Verbeek and Michael G. Schlossmacher

      Article first published online: 10 FEB 2016 | DOI: 10.1111/jnc.13390

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      Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α-synuclein (α-Syn), amyloid-β 1-42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested.

  5. Original Articles

    1. The relationship between glucocerebrosidase mutations and Parkinson disease

      Anna Migdalska-Richards and Anthony H. V. Schapira

      Article first published online: 10 FEB 2016 | DOI: 10.1111/jnc.13385

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      The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin–proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum-associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild-type GCase levels lead to a retardation of alpha-synuclein degradation via chaperone-mediated autophagy (CMA), which subsequently results in alpha-synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria.

      This article is part of a special issue on Parkinson disease.

  6. Editorial Highlights

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      Kurtosis imaging reveals microstructural changes of late-stage α-synuclein accumulation in a mouse model of Parkinson's disease

      Stephen Williams

      Article first published online: 1 FEB 2016 | DOI: 10.1111/jnc.13522

      This article is a critique of the paper by Khairnar et al. in the current issue of the Journal of Neurochemistry which describes the use of a sophisticated magnetic resonance imaging technique, diffusion kurtosis imaging, to investigate microstructural changes in the brain of TNWT-61 mice that are over-expressing α-synuclein. The importance of α-synuclein to Parkinson's disease pathology is considered and the article critically assessed. The steps needed to establish this method as a biomarker in human disease is discussed.

      Read the highlighted articleLate-stage α-synuclein accumulation in TNWT-61 mouse model of Parkinson's disease detected by diffusion kurtosis imaging’ on doi: 10.1111/jnc.13500.

  7. Original Articles

    1. Late-stage α-synuclein accumulation in TNWT-61 mouse model of Parkinson's disease detected by diffusion kurtosis imaging

      Amit Khairnar, Jana Ruda-Kucerova, Eva Drazanova, Nikoletta Szabó, Peter Latta, Anas Arab, Birgit Hutter-Paier, Daniel Havas, Manfred Windisch, Alexandra Sulcova, Zenon Starcuk Jr., András Király and Irena Rektorova

      Article first published online: 1 FEB 2016 | DOI: 10.1111/jnc.13500

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      We propose diffusion kurtosis imaging as a sensitive method for detecting human α-synuclein accumulation-induced changes in brain tissue, which may be reflective of Parkinson disease stage. Boxplots show the averaged mean kurtosis (orange) and mean diffusivity (blue) under the results of the analysis (*p < 0.05) in brains of wild-type (WT) and α-synuclein over-expressing (TNWT-61) mice. This approach might represent a novel biomarker for the early diagnosis of Parkinson's disease.

      Read the Editorial Highlight for this article on doi: 10.1111/jnc.13522.

    2. Docosahexaenoic acid (DHA) prevents corticosterone-induced changes in astrocyte morphology and function

      Gaëlle Champeil-Potokar, Marie Hennebelle, Alizée Latour, Sylvie Vancassel and Isabelle Denis

      Article first published online: 29 JAN 2016 | DOI: 10.1111/jnc.13510

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      We show that corticosterone increases the glutamate recycling capacity of rat cortical astrocytes in culture, and alters their morphology, which may be detrimental in the long term. Increasing the membrane incorporation of docosahexaenoic acid (DHA), the main omega-3 in brain, reduces the amount of glucocorticoid receptors (GR) and prevents the effects of corticosterone. This may help the astrocytes maintain a functional phenotype in chronic stress situations.

    3. You have full text access to this OnlineOpen article
      Acute selective serotonin reuptake inhibitors regulate the dorsal raphe nucleus causing amplification of terminal serotonin release

      Elyse C. Dankoski, Susan Carroll and Robert Mark Wightman

      Article first published online: 26 JAN 2016 | DOI: 10.1111/jnc.13528

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      In this work, stimulations of the dorsal raphe nucleus (DRN) evoke serotonin release that is recorded in the substantia nigra pars reticulata (SNpr) using in vivo fast-scan cyclic voltammetry. Systemic administration of a selective serotonin reuptake inhibitor (SSRI) causes both an increase in t1/2 and an increase in [5-HT]max in the SNpr. Local application of SSRI to the DRN recapitulates the increase in [5-HT]max observed in the SNpr without affecting uptake. Thus, SSRIs increase serotonin signaling via two distinct SERT-mediated mechanisms.

    4. Administration of low dose estrogen attenuates gliosis and protects neurons in acute spinal cord injury in rats

      Supriti Samantaray, Arabinda Das, Denise C. Matzelle, Shan P. Yu, Ling Wei, Abhay Varma, Swapan K. Ray and Naren L. Banik

      Article first published online: 26 JAN 2016 | DOI: 10.1111/jnc.13464

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      Experimental studies with low dose estrogen therapy in acute spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes. Estrogen has been found to ameliorate several degenerative pathways following SCI. Thus, such early protective effects may even lead to functional recovery in long term injury. Studies are underway in chronic SCI in a follow up manuscript.

  8. Editorial Highlights

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      Dissecting striatal adenosine-cannabinoid receptor interactions. New clues from rats over-expressing adenosine A2A receptors

      Sergi Ferré and Ana Maria Sebastião

      Article first published online: 25 JAN 2016 | DOI: 10.1111/jnc.13520

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      This Editorial highlights a study by Chiodi et al. () showing that the effects mediated by cannabinoid CB1 receptor (CB1R) activation in the striatum are significantly reduced in rats with neuronal over-expression of adenosine A2A receptors (A2AR). Two hypotheses are derived from that study. Hypothesis A: two subpopulations of pre-synaptic CB1R in corticostriatal glutamatergic terminals exist, one forming and another not forming heteromers with A2AR. Hypothesis B: CB1R are predominantly forming heteromers with A2AR. In the case of hypothesis A, the A2AR might be required for CB1R-A2AR heteromeric signaling, whereas non-heteromeric CB1R activity is inhibited by A2ARs. In the case of hypothesis B, up-regulation of A2ARs may perturb heteromeric stoichiometry, thus reducing CB1R functioning. In any case, pre-synaptic striatal A2AR-CB1R heteromers emerge as important targets of the effects of cannabinoids demonstrated at the neuronal and behavioral level.

      Read the highlighted articleStriatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors’ on doi: 10.1111/jnc.13421.

  9. Original Articles

    1. Validation of soluble amyloid-β precursor protein assays as diagnostic CSF biomarkers for neurodegenerative diseases

      Linda J.C. van Waalwijk van Doorn, Marleen J. Koel-Simmelink, Ute Haußmann, Hans Klafki, Hanne Struyfs, Philipp Linning, Hans-Joachim Knölker, Harry Twaalfhoven, H. Bea Kuiperij, Sebastiaan Engelborghs, Philip Scheltens, Marcel M. Verbeek, Eugeen Vanmechelen, Jens Wiltfang and Charlotte E. Teunissen

      Article first published online: 24 JAN 2016 | DOI: 10.1111/jnc.13527

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      We analytically validated the performance of assays detecting soluble amyloid-β precursor protein (sAPP) α and β in CSF according to SOPs in agreement with ISO15189 guidelines. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, this study proofs that the newly developed SOPs, with a minor modification, provide highly useful tools for the validation of new biomarker assays.

    2. Involvement of metabotropic glutamate receptor 5 in the inhibition of methamphetamine-associated contextual memory after prolonged extinction training

      Chien-Hsuan Huang, Yang-Jung Yu, Chih-Hua Chang and Po-Wu Gean

      Article first published online: 24 JAN 2016 | DOI: 10.1111/jnc.13525

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      Conditioning mice with methamphetamine place preference (METH CPP) increases surface expression of AMPA receptors (AMPARs) in the basolateral amygdala. We found prolongation of extinction duration from 6 to 10 days prevented priming effect. At the molecular level, we discovered that extensive extinction (EE) reversed the METH CPP-induced increase in surface expression of GluA2 and AMPA/NMDA ratio. In addition, we found that extinction with the metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training-elicited inhibition of METH-primed reinstatement is mediated by mGluR5 (PAM: positive allosteric modulator).

  10. Short Communications

    1. Shank3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of NMDA receptor levels at axon terminals

      Sonja Halbedl, Michael Schoen, Marisa S Feiler, Tobias M Boeckers and Michael J Schmeisser

      Article first published online: 24 JAN 2016 | DOI: 10.1111/jnc.13523

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      Shank1, Shank2, and Shank3 are major postsynaptic scaffold proteins of excitatory glutamatergic synapses strongly related to several neuropsychiatric disorders. However, a few studies have already implicated a functional role of the Shanks beyond the postsynaptic density (PSD). We here show that all three Shanks are localized in both axons and pre-synaptic specializiations of developing hippocampal neurons in culture. We further provide evidence that Shank3 is involved in the modulation of NMDA receptor levels at axon terminals. Taken together, our study will open up novel avenues for the future analysis of neuronal Shank biology in both health and disease.

  11. Original Articles

    1. Nucleus accumbens core dopamine signaling tracks the need-based motivational value of food-paired cues

      Tara J. Aitken, Venuz Y. Greenfield and Kate M. Wassum

      Article first published online: 24 JAN 2016 | DOI: 10.1111/jnc.13494

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      Food-predictive stimuli motivate food-seeking behavior. Here, we show that food cues evoke a robust nucleus accumbens core dopamine response when hungry that correlates with the cue's ability to invigorate general food seeking. This response is attenuated when sated, demonstrating that food cue-evoked accumbens dopamine responses are sensitive to the need state information that determines the current adaptive utility of cue-motivated action.

    2. Tryptophan-2,3-dioxygenase is regulated by prostaglandin E2 in malignant glioma via a positive signaling loop involving prostaglandin E receptor-4

      Katharina Ochs, Martina Ott, Katharina J. Rauschenbach, Katrin Deumelandt, Felix Sahm, Christiane A. Opitz, Andreas von Deimling, Wolfgang Wick and Michael Platten

      Article first published online: 22 JAN 2016 | DOI: 10.1111/jnc.13503

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      We proposed that in malignant gliomas prostaglandin E2 (PGE2) produced by cyclooxygenases (COX) up-regulates tryptophan-2,3-dioxygenase (TDO) expression and enzyme activity through binding to its Gs-coupled receptor EP4 and therefore may mediate tumor immune escape in part through aryl hydrocarbon receptor (AHR) activation. Moreover, TDO activity itself seems to induce intratumoral PGE2 metabolism suggesting an immunosuppressive loop involving COX/EP4/TDO.

    3. Dysbindin-1 modifies signaling and cellular localization of recombinant, human D3 and D2 receptors

      Nathalie Schmieg, Cristina Rocchi, Stefania Romeo, Roberto Maggio, Mark J. Millan and Clotilde Mannoury la Cour

      Article first published online: 21 JAN 2016 | DOI: 10.1111/jnc.13501

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      Dysbindin-1, a candidate gene for schizophrenia, alters D2 receptors cell surface expression. We demonstrate that dysbindin-1 expression also influences cell surface levels of D3 receptors. Further, Dysbindin-1 reduces DA-induced adenylate cylase recruitment/cAMP production and modifies major signaling pathways (Akt and extracellular signal-regulated kinases1/2 (ERK1/2)) of both D2 and D3 receptors. Dysbindin-1 modulates thus D2 and D3 receptor signaling, supporting a link to schizophrenia.

    4. Inhibition of p38 mitogen-activated protein kinase signaling reduces multidrug transporter activity and anti-epileptic drug resistance in refractory epileptic rats

      Yiye Shao, Cuicui Wang, Zhen Hong and Yinghui Chen

      Article first published online: 21 JAN 2016 | DOI: 10.1111/jnc.13498

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      We show that the specific inhibitor of p38MAPK could down-regulate the expression of multidrug transporter (P-glycoprotein) in blood–brain barrier, increase the concentration of antiepileptic drugs in the hippocampal extracellular fluid and reduce anti-epileptic drug resistance in refractory epileptic rats. We propose that the p38MAPK signaling pathway participates in drug resistance in refractory epilepsy through the regulation of P-glycoprotein expression.

    5. A potential therapeutic effect of saikosaponin C as a novel dual-target anti-Alzheimer agent

      Tae Ho Lee, Sungha Park, Mi-Hyeon You, Ji-Hong Lim, Sang-Hyun Min and Byeong Mo Kim

      Article first published online: 21 JAN 2016 | DOI: 10.1111/jnc.13515

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      Tau and amyloid beta are two key features in Alzheimer's disease. Saikosaponin C, an active component of Bupleuri Radix, inhibits abnormal tau phosphorylation and amyloid beta production, thereby promoting synaptic integrity. Saikosaponin C also prevents amyloid beta-induced apoptosis in brain vascular endothelial cells. Therefore, Saikosaponin C may provide a new therapeutic strategy for treatment of neurodegenerative diseases, including Alzheimer's disease.

    6. Synthesis of docosahexaenoic acid from eicosapentaenoic acid in retina neurons protects photoreceptors from oxidative stress

      María Victoria Simón, Daniela L. Agnolazza, Olga Lorena German, Andrés Garelli, Luis E. Politi, Martin-Paul Agbaga, Robert E. Anderson and Nora P. Rotstein

      Article first published online: 20 JAN 2016 | DOI: 10.1111/jnc.13487

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      Docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in retina photoreceptors, and its precursor, eicosapentaenoic acid (EPA) have multiple beneficial effects. Here, we show that retina neurons in vitro express the desaturase FADS2 and can synthesize DHA from EPA. Moreover, addition of EPA to these cultures protects photoreceptors from oxidative stress and promotes their differentiation through its metabolization to DHA.

    7. Central kynurenine pathway shift with age in women

      Josien de Bie, Jade Guest, Gilles J. Guillemin and Ross Grant

      Article first published online: 20 JAN 2016 | DOI: 10.1111/jnc.13496

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      Both the inflammation marker neopterin and kynurenine pathway activity were increased with age in the CSF of female subjects. While levels of quinolinic acid (QUIN), picolinic acid (PIC), kynurenine and quinaldic acid (QA) were increased, 3-hydroxykynurenine (3HK) was decreased and 3-hydroxyanthranilic acid (3HAA) and kynurenic acid (KYNA) remained unchanged. Of particular interest is the increase in QUIN, a neuroexcitotoxin associated with neurodegeneration.

    8. Selective up-regulation of functional mu-opioid receptor splice variants by chronic opioids

      Sumita Chakrabarti, Priyanka A. Madia and Alan R. Gintzler

      Article first published online: 20 JAN 2016 | DOI: 10.1111/jnc.13519

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      In the spinal cord of males, but not females, chronic morphine up-regulates mRNA encoding two mu-opioid receptor (MOR) variants, MOR-1B2 and MOR-1C1 (MOR-1B2/-1C1). We now demonstrate that chronic treatment with the clinically relevant opioids morphine, hydrocodone or oxycodone up-regulates MOR-1B2/-1C1 functional protein, which is dependent on de novo protein synthesis. Findings underscore the importance of unique signaling attributes of MOR variants to sexually dimorphic tolerance mechanisms.

    9. Fluoxetine induces vascular endothelial growth factor/Netrin over-expression via the mediation of hypoxia-inducible factor 1-alpha in SH-SY5Y cells

      Jiayi Wang, Xiaoyu Zhou, Haiyan Lu, Mingrui Song, Jinglong Zhao and Qiaoshu Wang

      Article first published online: 20 JAN 2016 | DOI: 10.1111/jnc.13521

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      We show that hypoxia-inducible factor 1-alpha (HIF-1α) regulates transcription of both vascular endothelial growth factor (VEGF) and Netrin. Furthermore, we also show that in hypoxia fluoxetine up-regulates VEGF and Netrin expression via mediation of HIF-1α that binds to hypoxia-response element (HRE) sites of VEGF and Netrin promoters. Our study indicates that HIF-1α may play an important role in the treatment of cerebral infarction through mediating the recovery of neurological function induced by fluoxetine. These findings provide a theoretical basis for development of gene therapeutic drugs targeting HIF-1α.

    10. Sign-trackers have elevated myo-inositol in the nucleus accumbens and ventral hippocampus following Pavlovian conditioned approach

      Christopher J. Fitzpatrick, Shane A. Perrine, Farhad Ghoddoussi, Matthew P. Galloway and Jonathan D. Morrow

      Article first published online: 19 JAN 2016 | DOI: 10.1111/jnc.13524

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      Sign-tracking rats preferentially approach reward cues during Pavlovian conditioning, while goal-trackers instead approach the location of impending reward. Sign-trackers are also more prone to cue-induced drug-seeking behavior. We used magnetic resonance spectroscopy to show that myo-inositol levels are higher in the ventral hippocampus and nucleus accumbens of sign-trackers relative to goal-trackers. Thus, elevated myo-inositol may be a vulnerability factor for addiction.

    11. 3,4-methylenedioxymethamphetamine increases excitability in the dentate gyrus: role of 5HT2A receptor-induced PGE2 signaling

      Stuart A. Collins, Courtney Huff, Nicolas Chiaia, Gary A. Gudelsky and Bryan K. Yamamoto

      Article first published online: 19 JAN 2016 | DOI: 10.1111/jnc.13493

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      We hypothesized that the widely abused psychostimulant MDMA causes a loss of parvalbumin (PV) cells and increases excitability in the dentate gyrus. MDMA increases serotonin (5HT) release and activates 5HT2A receptors. The increased activation of 5HT2A receptors promotes the production of prostaglandin E2 (PGE2) and subsequent activation of EP1 receptors in the dentate gyrus. EP1 receptor activation leads to eventual excitotoxicity and loss of PV interneurons resulting in reduced inhibition and lowered seizure threshold resulting in increased seizure susceptibility.

    12. Calcium/calmodulin-dependent kinase II activity is required for maintaining learning-induced enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic excitation

      Sourav Ghosh, Iris Reuveni, Edi Barkai and Raphael Lamprecht

      Article first published online: 18 JAN 2016 | DOI: 10.1111/jnc.13505

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      We show that training rats in a complex olfactory discrimination task leads to the enhancement of averaged amplitude of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) in piriform cortex pyramidal neurons for days after learning. Inhibiting calcium/calmodulin-dependent kinase II (CaMKII) using KN93 or tatCN21 days after learning, reduced the averaged mEPSC amplitude in neurons in piriform cortex of trained rats to the level where they are not significantly different from mEPSC of control animals. CaMKII inhibition leads to a decrease in AMPAR single channel conductance. We conclude that the maintenance of learning-induced enhancement of AMPAR-mediated synaptic excitation requires the activity of CaMKII.

    13. Nicastrin is required for amyloid precursor protein (APP) but not Notch processing, while anterior pharynx-defective 1 is dispensable for processing of both APP and Notch

      Chen Hu, Linlin Zeng, Ting Li, Michael A. Meyer, Mei-Zhen Cui and Xuemin Xu

      Article first published online: 17 JAN 2016 | DOI: 10.1111/jnc.13518

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      There are unanswered questions regarding the roles of each component of the γ-secretase complex in amyloid precursor protein (APP) and Notch processing. The most relevant, novel finding of this study is that nicastrin (NCT) is required for APP but not Notch processing, while Aph-1 is not essential for processing of both APP and Notch, suggesting NCT as a therapeutic target to restrict Aβ formation without impairing Notch signaling.

    14. Region-specific rapid regulation of aromatase activity in zebra finch brain

      Devon Comito, Devaleena S. Pradhan, Branden J. Karleen and Barney A. Schlinger

      Article first published online: 14 JAN 2016 | DOI: 10.1111/jnc.13513

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      Aromatase activity in male and female zebra finch hippocampus, hypothalamus, and caudomedial nidopallium is rapidly regulated by Ca2+-dependent phosphorylation. Low ATP and Mg2+ decrease activity, whereas nicotinamide adenine dinucleotide phosphate (NADPH), high ATP, and inhibition of protein kinase C increase activity. Evidence suggests this may occur at the synapse. These results provide a mechanism for rapid regulation of behavior via brain estrogen synthesis.

    15. Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo

      Rashed Harun, Kristin M. Hare, Elizabeth M. Brough, Miranda J. Munoz, Christine M. Grassi, Gonzalo E. Torres, Anthony A. Grace and Amy K. Wagner

      Article first published online: 13 JAN 2016 | DOI: 10.1111/jnc.13444

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      L-DOPA is commonly used to treat Parkinsonian symptoms, but little is known about how it affects presynaptic DA neurotransmission. Using in vivo fast-scan cyclic voltammetry, we show L-DOPA inhibits DA reuptake in a region-specific and dose-dependent manner, and L-DOPA has paradoxical effects on release. These findings may be important when considering mechanisms for L-DOPA's therapeutic benefits and adverse side-effects.

    16. Adenosine A1 receptors control the metabolic recovery after hypoxia in rat hippocampal slices

      João M. N. Duarte, Rodrigo A. Cunha and Rui A. Carvalho

      Article first published online: 13 JAN 2016 | DOI: 10.1111/jnc.13512

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      This study demonstrates that tonic activation of adenosine A1 receptors (A1R) plays an important role in the reoxygenation recovery of the metabolic alterations caused by transient hypoxia in rat hippocampal slices. This ability of A1R to inhibit neuronal metabolism may be a key mechanism by which adenosine affords neuroprotection upon acute hypoxia, thus preventing the long-term impairment of neuronal circuits.

    17. Dopamine induces mitochondrial depolarization without activating PINK1-mediated mitophagy

      Heather Bondi, Mara Zilocchi, Maria Gabriella Mare, Gianluca D'Agostino, Stefano Giovannardi, Santiago Ambrosio, Mauro Fasano and Tiziana Alberio

      Article first published online: 13 JAN 2016 | DOI: 10.1111/jnc.13506

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      Impaired dopamine (DA) homeostasis and oxidative stress play a key role in the pathogenesis of Parkinson's disease. Free cytosolic dopamine undergoes spontaneous oxidation and generates semiquinonic and quinonic species (DAQ) with the concurrent production of reactive oxygen species (ROS). Dopamine dissipates mitochondrial potential (Δψm) with a peculiar alteration of the mitochondrial network. However, PINK1-dependent mitophagy is not activated by dopamine toxicity and dysfunctional mitochondria accumulate inside the cell.

    18. In vivo and in vitro effects of multiple sclerosis immunomodulatory therapeutics on glutamatergic excitotoxicity

      Dirk Luchtman, René Gollan, Erik Ellwardt, Jérôme Birkenstock, Kerstin Robohm, Volker Siffrin and Frauke Zipp

      Article first published online: 11 JAN 2016 | DOI: 10.1111/jnc.13456

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      Evidence suggests MS pathogenesis may involve neuronal excitotoxicity, induced by local release of glutamate. However, current MS drugs, including dimethyl fumerate (DMF) and fingolimod (FTY720) are largely anti-inflammatory and not yet fully tested for their neuroprotective potential. Here, we show that the drugs, in particular DMF metabolite monomethyl fumerate (MMF), protect neurons by excitotoxicity modulating effects. Th17, T-helper 17.

    19. Glyceraldehyde 3-phosphate dehydrogenase augments the intercellular transmission and toxicity of polyglutamine aggregates in a cell model of Huntington disease

      Elena R. Mikhaylova, Vladimir F. Lazarev, Alina D. Nikotina, Boris A. Margulis and Irina V. Guzhova

      Article first published online: 11 JAN 2016 | DOI: 10.1111/jnc.13463

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      Aggregating polygluatmine tracts were shown to release from the cells over-expressing mutant huntingtin in a complex with glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The enzyme enhances the intracellular transport of aggregates to healthy cells, prionization of normal cellular proteins and finally cell death, thus demonstrating the pivotal role of GAPDH in the horizontal transmission of neurodegeneration.

    20. You have full text access to this OnlineOpen article
      Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) reduces neonatal hypoxic-ischaemic brain damage

      Mariya Hristova, Eridan Rocha-Ferreira, Xavier Fontana, Laura Thei, Rheanan Buckle, Melina Christou, Supanida Hompoonsup, Naomi Gostelow, Gennadij Raivich and Donald Peebles

      Article first published online: 11 JAN 2016 | DOI: 10.1111/jnc.13490

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      Current data show that neuronal and astroglial STAT3 molecules are involved in the pathways underlying cell death, tissue loss and gliosis following neonatal hypoxia-ischaemia, but differ with respect to the target of their effect. Y705-phosphorylation contributes to hypoxic-ischaemic histopathology. Protective effects of STAT3 inactivation make it a possible target for a therapeutic strategy in neonatal hypoxia-ischaemia.

    21. Attenuated presenilin-1 endoproteolysis enhances store-operated calcium currents in neuronal cells

      Maria Ryazantseva, Ksenia Skobeleva, Lyubov Glushankova and Elena Kaznacheyeva

      Article first published online: 11 JAN 2016 | DOI: 10.1111/jnc.13495

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      Reduced endoproteolysis levels of presenilin-1 (PS1) have been detected in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Significant enhancement of SOC channel activation has been detected by electrophysiological measurements in cells with reduced PS1 endoproteolysis. The data obtained shed light on Alzheimer's disease pathogenesis and implicates to the future drugs development.

    22. You have free access to this content
      Regulation of cyclic AMP response element-binding protein during neuroglial interactions

      LiMei Qin, Ron Bouchard and Subbiah Pugazhenthi

      Article first published online: 11 JAN 2016 | DOI: 10.1111/jnc.13497

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      Neuroglial interactions were examined using coculture models of human neuroprogenitor cell-derived neurons and microglia isolated from human fetal brain. A novel coculture model of neurons and microglia cultured on ACLAR membranes in the same dish was also included. In this model, over-expression of the dominant negative mutant form of the transcription factor CREB in neurons induced neuronal apoptosis and microglial activation whereas expression of the wild type form of CREB resulted in protection of neurons and suppressed microglial activity, thereby suggesting that neurons play an active role in neuroglial interactions.

    23. Intraventricular apolipoprotein ApoJ infusion acts protectively in Traumatic Brain Injury

      Zhijian Huang, Chongjie Cheng, Li Jiang, Zhanyang Yu, Fang Cao, Jianjun Zhong, Zongduo Guo and Xiaochuan Sun

      Article first published online: 8 JAN 2016 | DOI: 10.1111/jnc.13491

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      Apolipoprotein J (ApoJ) was up-regulated after controlled cortical impact (CCI). Mice infused with human recombinant ApoJ prior to CCI showed reduced expression of complement and oxidative marker proteins as well as reduced inflammatory response and attenuated blood–brain barrier (BBB) disruption and cerebral edema. Neuronal maintenance and behavioral performance were improved by ApoJ infusion. These findings demonstrated the protective function of ApoJ for traumatic brain injury (TBI) therapy.

  12. Short Communications

    1. CD200 increases alternatively activated macrophages through cAMP-response element binding protein – C/EBP-beta signaling

      Kazuhide Hayakawa, Xiaohua Wang and Eng H. Lo

      Article first published online: 6 JAN 2016 | DOI: 10.1111/jnc.13492

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      We showed that CD200 treatment decreased pro-inflammatory cytokines (IL-1β, IL-6, and GM-CSF) along with suppressed inflammatory NF-κB activity in pro-inflammatory Mφ. On the other hand, CD200 increased Arg1, TGM2, and TGF-β production through CREB-C/EBPβ signaling. We think that these findings provide proof-of-concept that CD200 signaling may play a key role in regulating macrophage polarization toward anti-inflammatory phenotypes.

  13. Original Articles

    1. Proximity of SCG10 and prion protein in membrane rafts

      Yoshifumi Iwamaru, Hiroshi Kitani, Hiroyuki Okada, Takato Takenouchi, Yoshihisa Shimizu, Morikazu Imamura, Kohtaro Miyazawa, Yuichi Murayama, Edward A. Hoover and Takashi Yokoyama

      Article first published online: 27 DEC 2015 | DOI: 10.1111/jnc.13488

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      By applying a novel biochemical labeling method against detergent-resistant membrane fractions from mouse neuroblastoma cells, the neuron-specific microtubule-destabilization protein, SCG10 was identified as a novel candidate that is proximate to normal prion protein (PrP) in membrane rafts. SCG10 seemed unrelated to disease-related PrP formation under certain conditions, while there is a possible association between SCG10 levels and prion neuropathogenesis.

    2. You have free access to this content
      Metabolic, synaptic and behavioral impact of 5-week chronic deep brain stimulation in hemiparkinsonian rats

      Carine Chassain, Christophe Melon, Pascal Salin, Flora Vitale, Sébastien Couraud, Franck Durif, Lydia Kerkerian-Le Goff and Paolo Gubellini

      Article first published online: 21 DEC 2015 | DOI: 10.1111/jnc.13438

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      We studied the effects of chronic (5 weeks) continuous subthalamic nucleus (STN) high-frequency stimulation (HFS) in hemiparkinsonian rats. The levels of glutamate and GABA in the striatum (image) and substantia nigra reticulata (SNr) (image), measured by in vivo proton magnetic resonance spectroscopy (1H-MRS), were increased by 6-hydroxydopamine (6-OHDA) lesion, which also disrupted corticostriatal synaptic plasticity (image) and impaired forepaw skill (image) in the staircase test. Five-week STN HFS normalized glutamate and GABA levels and restored both synaptic plasticity and motor function. A partial behavioral recovery was observed at 2-week STN HFS.

    3. Striatal adenosine–cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors

      Valentina Chiodi, Antonella Ferrante, Luca Ferraro, Rosa Luisa Potenza, Monica Armida, Sarah Beggiato, Antonella Pèzzola, Michael Bader, Kjell Fuxe, Patrizia Popoli and Maria Rosaria Domenici

      Article first published online: 24 NOV 2015 | DOI: 10.1111/jnc.13421

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      We studied A2A-CB1 receptor interaction in transgenic rats over-expressing adenosine A2A receptors under the control of the neuron-specific enolase promoter (NSEA2A). In these rats, we demonstrated a reduced effect of the CB1 receptor agonist WIN 55,212-2 in the modulation of corticostriatal synaptic transmission and locomotor activity, while CB1 receptor expression level did not change with respect to WT rats. A reduction in the expression of A2A-CB1 receptor heteromers is postulated.

  14. Reviews

    1. You have free access to this content
      Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies

      Anna Villar-Piqué, Tomás Lopes da Fonseca and Tiago Fleming Outeiro

      Article first published online: 11 SEP 2015 | DOI: 10.1111/jnc.13249

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      Alpha-synuclein is the speculated cornerstone of several neurodegenerative disorders known as Synucleinopathies. Nevertheless, the mechanisms underlying the pathogenic effects of this protein remain unknown. Here, we review the recent findings in the three corners of alpha-synuclein biology – structure, function and toxicity – and discuss the enigmatic roads that have accompanied alpha-synuclein from the beginning.

    2. You have free access to this content
      Genes associated with Parkinson's disease: regulation of autophagy and beyond

      Alexandra Beilina and Mark R Cookson

      Article first published online: 3 SEP 2015 | DOI: 10.1111/jnc.13266

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      Beilina and Cookson review the links between genes for Parkinson's disease (red) and the autophagy–lysosomal system. They propose the hypothesis that many of the known PD genes can be assigned to pathways that affect (I) turnover of mitochondria via mitophagy (II) turnover of several vesicular structures via macroautophagy or chaperone-mediated autophagy or (III) general lysosome function.


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