Journal of Neurochemistry

Cover image for Vol. 135 Issue 2

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: 55/252 (Neurosciences); 72/289 (Biochemistry & Molecular Biology)

Online ISSN: 1471-4159


  1. 1 - 67
  1. Original Articles

    1. Early metabolic responses to lithium/pilocarpine-induced status epilepticus in rat brain

      Imran Imran, Markus H. Hillert and Jochen Klein

      Article first published online: 8 OCT 2015 | DOI: 10.1111/jnc.13360

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      Status epilepticus (SE) was induced in rats by lithium–pilocarpine (‘Pilo’) administration, and extracellular metabolites were measured by microdialysis. Seizures caused several-fold increases in lactate levels which were attenuated by diazepam (‘Diaz’), ketamine, atropine and tetrodotoxin (TTX). Indicators of oxidative stress and membrane damage were also increased during seizures. Omission of calcium and pregabalin, a calcium channel blocker, reduced cellular damage induced by SE.

  2. Short Communications

    1. Sipa1l3/SPAR3 is targeted to postsynaptic specializations and interacts with the Fezzin ProSAPiP1/Lzts3

      Anna Dolnik, Noreen Kanwal, Sarah Mackert, Sonja Halbedl, Christian Proepper, Juergen Bockmann, Michael Schoen, Tobias M Boeckers, Susanne J Kühl and Michael J Schmeisser

      Article first published online: 8 OCT 2015 | DOI: 10.1111/jnc.13353

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      Spine-associated RapGAPs (SPARs) are essential modulators of synaptic signaling. Our study is the first to characterize the SPAR family member Sipa1l3/SPAR3 in neuronal tissue. We show that Sipa1l3/SPAR3 is conserved across species, has a distinct expression pattern in brain and is localized to excitatory postsynapses via its C-terminus, which represents an interaction module for other postsynaptic proteins including the Fezzin ProSAPiP1/Lzts3.

  3. Original Articles

    1. Sulforaphane is anticonvulsant and improves mitochondrial function

      Catalina Carrasco-Pozo, Kah Ni Tan and Karin Borges

      Article first published online: 8 OCT 2015 | DOI: 10.1111/jnc.13361

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      Sulforaphane was anticonvulsant in two acute mouse models of epilepsy and protected mice against pilocarpine-induced status epilepticus (SE). We also found antioxidant effects of sulforaphane in mouse plasma and hippocampal formations, exhibited by increased catalase and superoxide dismutase (SOD) activity, as well as increased abilities of hippocampal mitochondria to produce ATP. These effects likely underlie sulforaphane's anticonvulsant mechanisms of action.

    2. Establishment and characterization of a new conditionally immortalized human astrocyte cell line

      Tomomi Furihata, Ryo Ito, Atsuko Kamiichi, Kosuke Saito and Kan Chiba

      Article first published online: 8 OCT 2015 | DOI: 10.1111/jnc.13358

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      In vitro astrocyte models are valuable experimental tools in various astrocyte studies. Here, we report the establishment of a new human astrocyte cell line, HASTR/ci35, which show various key astrocyte properties, including astrocytic transporter activities, glycogen storage and facilitation of neuronal cell differentiation. Thus, HASTR/ci35 is expected to significantly contribute to advances toward detailed understanding of human astrocyte functions.

    3. Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

      Zhiwei Tang, Shiping Li, Pengcheng Han, Junxiang Yin, Yan Gan, Qingwei Liu, Jinkun Wang, Chongqian Wang, Yu Li and Jiong Shi

      Article first published online: 8 OCT 2015 | DOI: 10.1111/jnc.13359

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      In ischemic stroke, excessive glutamate binds to AMPA receptor that depolarizes calcium channel and/ or NMDA receptor. Both of them allow calcium to enter the cell. The overload of calcium triggers cellular cascade that includes Caspase activation and release, leading to pre-mature cell death. We have demonstrated that PTx, a G-protein inhibitor, blocks calcium entry which in turn prevents further cellular damage.

    4. Acrolein contributes to TRPA1 up-regulation in peripheral and central sensory hypersensitivity following spinal cord injury

      Jonghyuck Park, Lingxing Zheng, Glen Acosta, Sasha Vega-Alvarez, Zhe Chen, Breanne Muratori, Peng Cao and Riyi Shi

      Article first published online: 8 OCT 2015 | DOI: 10.1111/jnc.13352

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      We propose that the trauma-mediated elevation of acrolein causes neuropathic pain through at least two mechanisms: acrolein stimulates the production of transient receptor protein ankyrin 1 (TRPA1) in both central and peripheral locations, and it activates TRPA1 channels directly. Therefore, acrolein appears to be a critical factor in the pathogenesis of post-SCI sensory hypersensitivity, becoming a novel therapeutic target to relieve both acute and chronic post-SCI neuropathic pain.

    5. Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y

      Esther L. Sabban, Marcela Laukova, Lishay G. Alaluf, Emelie Olsson and Lidia I. Serova

      Article first published online: 30 SEP 2015 | DOI: 10.1111/jnc.13347

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      Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze (EPM), with elevated mRNA for NE biosynthetic enzymes in subset of animals.

  4. Reviews

    1. You have free access to this content
      Endogenous recovery after brain damage: molecular mechanisms that balance neuronal life/death fate

      Luis B. Tovar-y-Romo, Andrés Penagos-Puig and Josué O. Ramírez-Jarquín

      Article first published online: 29 SEP 2015 | DOI: 10.1111/jnc.13362

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      Under neurodegenerative conditions, endogenously activated mechanisms balance out molecular cues that determine whether neurons contend toxicity or die. Many processes involved in endogenous repair may as well lead to tissue damage depending on the strength of stimuli. Signaling mediated by trophic factors and neuroinflammation are examples of these processes as they regulate different mechanisms that mediate neuronal demise including necrosis, apoptosis, necroptosis, pyroptosis and autophagy. In this review, we discuss recent findings on balanced regulation and their involvement in neuronal death.

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      Main path and byways: non-vesicular glutamate release by system xc as an important modifier of glutamatergic neurotransmission

      Ann Massie, Séverine Boillée, Sandra Hewett, Lori Knackstedt and Jan Lewerenz

      Article first published online: 29 SEP 2015 | DOI: 10.1111/jnc.13348

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      System xc constitutes an important source of extrasynaptic glutamate in the brain. By modulating the tone of extrasynaptic metabotropic or ionotropic glutamate receptors, it affects excitatory neurotransmission, the threshold for overexcitation and excitotoxicity and, as a consequence, behavior. This review describes the current knowledge of how system xc is regulated and involved in physiological as well as pathophysiological brain functioning.

  5. Original Articles

    1. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone

      Liangliang Zhao, Majda Hadziahmetovic, Chenguang Wang, Xueying Xu, Ying Song, H.A. Jinnah, Jolanta Wodzinska, Jared Iacovelli, Natalie Wolkow, Predrag Krajacic, Alyssa Cwanger Weissberger, John Connelly, Michael Spino, Michael K. Lee, James Connor, Benoit Giasson, Z. Leah Harris and Joshua L. Dunaief

      Article first published online: 29 SEP 2015 | DOI: 10.1111/jnc.13292

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      Above: Iron (Fe) normally moves from capillaries to glia to neurons. It is exported from the glia by ferroportin (Fpn) with ferroxidases ceruloplasmin (Cp) and/or Hephaestin (Heph). Below: In mice with mutation of Cp and Heph, iron accumulates in glia, while neurons have low iron levels. Both neurons and glia degenerate and mice become ataxic unless given an iron chelator.

    2. Regulation of the orexigenic neuropeptide, enkephalin, by PPARδ and fatty acids in neurons of the hypothalamus and forebrain

      Kinning Poon, Mohammad Alam, Olga Karatayev, Jessica R. Barson and Sarah F. Leibowitz

      Article first published online: 29 SEP 2015 | DOI: 10.1111/jnc.13298

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      Our findings show that PPARδ in forebrain and hypothalamic neurons negatively regulates enkephalin (ENK), a peptide known to promote ingestive behavior. This inverse relationship is consistent with our additional findings, that a saturated (palmitic; PA) compared to a monounsaturated fatty acid (oleic; OA) has a strong stimulatory effect on ENK and weak effect on PPARδ. These results suggest that PPARδ protects against the neuronal effects of fatty acids, which differentially affect neurochemical systems involved in ingestive behavior.

    3. Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aβ42 and influence of disease on the total-Aβ42/Aβ40 ratio

      J. Randall Slemmon, Alice Shapiro, Marc Mercken, Johannes Streffer, Gary Romano, Niels Andreasen, Henrik Zetterberg and Kaj Blennow

      Article first published online: 29 SEP 2015 | DOI: 10.1111/jnc.13297

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      Aβ1-42 measurement in CSF has provided an important tool for early detection of AD. However, it appears that most assays measure a free fraction of Aβ1-42. This study examined total extracted Aβ1-42, since this would provide a more accurate assessment of Aβ1-42 in AD CSF. Total Aβ1-42 measurements alone were not good for detecting AD but total Aβ1-42/Aβ1-40 performed well.

    4. Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway

      Juan Deng, Ahsan Habib, Demian F. Obregon, Steven W. Barger, Brian Giunta, Yan-Jiang Wang, Huayan Hou, Darrell Sawmiller and Jun Tan

      Article first published online: 24 SEP 2015 | DOI: 10.1111/jnc.13351

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      Hypothesized pathway for sAPPα-mediated reduction of tau phosphorylation: Soluble amyloid precursor protein alpha (sAPPα) increases glycogen synthase kinase 3 beta (GSK3β) inhibitory phosphorylation by inhibiting β-site APP-converting enzyme 1 (BACE1) and followed by reduction of tau phosphorylation. BACE1 inhibition also results in a decrease of amyloid-beta (Aβ) production. We believe these findings might provide a new strategy to use sAPPα, in treating both Aβ and tau pathology.

    5. Adenosine A2A receptors permit mGluR5-evoked tyrosine phosphorylation of NR2B (Tyr1472) in rat hippocampus: a possible key mechanism in NMDA receptor modulation

      Konstantinos Sarantis, Eirini Tsiamaki, Stylianos Kouvaros, Costas Papatheodoropoulos and Fevronia Angelatou

      Article first published online: 24 SEP 2015 | DOI: 10.1111/jnc.13291

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      We propose the following molecular mechanism by which metabotropic Glutamate Receptor 5 (mGluR5) potentiate ionotropic Glutamate N-Methyl-D-Aspartate Receptor (NMDAR) responses in rat hippocampus. Co-activation of mGLUR5/NMDAR activates Src kinases, leading to NR2B(Tyr1472) phosphorylation, which anchors NR2B-containing NMDAR to the plasma membrane, thus inducing a robust increase in the NMDA-dependent excitability. Interestingly, adenosine A2A receptors license the mGluR5-induced NR2B(Tyr1472) phosphorylation.

    6. A new role for AMP-activated protein kinase in the circadian regulation of L-type voltage-gated calcium channels in late-stage embryonic retinal photoreceptors

      Cathy C.Y. Huang, Liheng Shi, Chia-Hung Lin, Andy Jeesu Kim, Michael L. Ko and Gladys Y.-P. Ko

      Article first published online: 22 SEP 2015 | DOI: 10.1111/jnc.13349

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      We found that in chicken embryonic retina, the activation of AMP-activated protein kinase (AMPK) is under circadian control and anti-phase to the retinal ATP rhythm. While ATP content is higher at night, phosphorylated AMPK (pAMPK) is higher during the day. AMPK appears to be upstream of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and mammalian target of rapamycin complex 1 (mTORC1) but downstream of adenylyl cyclase in regulating the circadian rhythm of L-VGCCs. Therefore, as a cellular energy sensor, AMPK integrates into the cell signaling network to regulate the circadian rhythm of photoreceptor physiology.

    7. Nicotinic acetylcholine receptors mediate donepezil-induced oligodendrocyte differentiation

      Osamu Imamura, Masaaki Arai, Minori Dateki, Toru Ogata, Ryuji Uchida, Hiroshi Tomoda and Kunio Takishima

      Article first published online: 22 SEP 2015 | DOI: 10.1111/jnc.13294

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      We show that donepezil, a drug for the treatment of Alzheimer disease, can stimulate oligodendrocyte differentiation and maturation of oligodendrocyte progenitor cells. Transcripts for essential myelin-associated genes, such as PLP, MAG, MBP, CNPase and MOG in addition to transcripton factors that regulate oligodendrocyte differentiation and myelination were rapidly increased after treatment with donepezil. These effects were partly dependent on nicotinic acetylcholine receptor (nAChR).

  6. Short Communications

    1. Long-lasting effect of NMDA receptor antagonist memantine on ethanol-cue association and relapse

      Valentina Vengeliene, Anastasia Olevska and Rainer Spanagel

      Article first published online: 22 SEP 2015 | DOI: 10.1111/jnc.13350

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      Our data supports the possibility that memantine is a treatment option for alcoholism. However, the effectiveness of this drug seems to lie in its ability to disrupt conditioned behaviours and should be given in conjunction with exposure to conditioned drug stimuli.

  7. Original Articles

    1. Protease activated receptor-1 antagonist ameliorates the clinical symptoms of experimental autoimmune encephalomyelitis via inhibiting breakdown of blood–brain barrier

      Ha Neui Kim, Yu Ri Kim, Sung Min Ahn, Sun Kyung Lee, Hwa Kyoung Shin and Byung Tae Choi

      Article first published online: 22 SEP 2015 | DOI: 10.1111/jnc.13285

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      In the experimental autoimmune encephalomyelitis (EAE) mice model, treatment with two protease activated receptor-1 (PAR-1) antagonists KC-A0590 and SCH-530348 resulted in stabilization of vascular endothelial cells and reduced blood–brain barrier (BBB) breakdown with down-regulated expression of matrix metalloproteinase-9 (MMP-9) and preserved expression of occludin and zonula occludens (ZO)-1. PAR-1 antagonist is effective in attenuation of the clinical symptoms of EAE mice by inhibiting breakdown of BBB.

    2. Cannabinoid receptor type 1 agonist ACEA improves motor recovery and protects neurons in ischemic stroke in mice

      Laura Caltana, Trinidad Maria Saez, María Paula Aronne and Alicia Brusco

      Article first published online: 18 SEP 2015 | DOI: 10.1111/jnc.13288

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      ACEA improved the motor activity affected by the middle cerebral artery occlusion. At histologic level, ACEA preserved the neuronal cytoarchitecture, decreased the astroglial and microglial reaction.

    3. Comparison of dopamine kinetics in the larval Drosophila ventral nerve cord and protocerebrum with improved optogenetic stimulation

      Eve Privman and B. Jill Venton

      Article first published online: 18 SEP 2015 | DOI: 10.1111/jnc.13286

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      We use a new optogenetic tool, red light activated CsChrimson, to stimulate the release of dopamine in the ventral nerve cord and medial protocerebrum of the larval Drosophila central nervous system. We monitored extracellular dopamine by fast scan cyclic voltammetry and used Michaelis-Menten modeling to probe the regulation of extracellular dopamine, discovering important similarities and differences in these two regions.

  8. Editorial Highlights

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      Parkinson's disease, anxious depression and serotonin – zooming in on hippocampal neurogenesis

      Robert Blum and Klaus-Peter Lesch

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13278

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      This Editorial highlights a study by Deusser et al. (2015) published in this issue of J Neurochem. In a mouse model of Parkinson's disease (PD), the authors observed a topographically restricted reduction in serotonergic fibres in the subgranular zone of the dentate gyrus. This phenotype was observed close to the neurogenic niche and was accompanied by an impaired fluoxetine response of hippocampal neuroblasts. In conclusion, alpha-synuclein inclusions in the serotonergic system may account for anxiety and depression symptoms in PD. DCX, doublecortin; GFAP, glial fibrillary acidic protein.

      Read the full article ‘Serotonergic dysfunction in the A53T alpha-synuclein mouse model of Parkinson's disease’ on doi: 10.1111/jnc.13253

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      Blood–brain barrier and brain fatty acid uptake: Role of arachidonic acid and PGE2

      Eric J. Murphy

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13289

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      How do fatty acids enter the brain and what role, if any, do membrane and cytosolic fatty acid binding proteins have on facilitating this process? This is a fundamental question that many lipid neurochemists will freely admit they cannot answer in any kind of definitive manner. A study by Dalvi and colleagues in this issue of the Journal of Neurochemistry now adds to our knowledge in this field. Among other important observations, their experiments demonstrate that a physiological level of arachidonic acid (ARA), that could be associated with many different physiological and pathophysiological states, increases permeability in a model of the human blood brain barrier (BBB) in the absence of cytokines. This last point is very important as it suggests increases in BBB permeability may occur in situations other than those associated with increases in tumor necrosis factor a (TNFinline image) and interleukin1b (IL1inline image), giving additional options for developing drugs impacting BBB permeability.

      Read the full articleExogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors’ on doi: 10.1111/jnc.13117

  9. Short Communications

    1. Distinct binding of amyloid imaging ligands to unique amyloid-β deposited in the presubiculum of Alzheimer's disease

      Bin Ji, Chun-Jen Chen, Kazunori Bando, Hiroki Ashino, Hideaki Shiraishi, Hiroaki Sano, Hiroyuki Kasahara, Takao Minamizawa, Kazutaka Yamada, Maiko Ono, Ming-Rong Zhang, Chie Seki, Lars Farde, Tetsuya Suhara and Makoto Higuchi

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13293

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      Non-invasive determination of amyloid-β peptide (Aβ) serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). We found that there are at least two different amyloid components in hippocampal CA1 and presubiculum providing distinct binding sites for the current amyloid radioligands. Comparative analysis for radioligand binding in these two regions could serve for developing novel imaging agents selectively visualizing neurotoxicity-related Aβ pathologies.

  10. Original Articles

    1. Down-regulation of BDNF in cell and animal models increases striatal-enriched protein tyrosine phosphatase 61 (STEP61) levels

      Jian Xu, Pradeep Kurup, Garikoitz Azkona, Tyler D. Baguley, Ana Saavedra, Angus C. Nairn, Jonathan A. Ellman, Esther Pérez-Navarro and Paul J. Lombroso

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13295

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      Altered expression of BDNF and STEP61 has been implicated in several neurological disorders. BDNF and STEP61 are known to regulate synaptic strengthening, but in opposite directions. Here, we report that reduced BDNF signaling leads to elevation of STEP61 both in BDNF+/− mice and after acute BDNF knockdown in cortical cultures. In contrast, activation of TrkB receptor results in the degradation of STEP61 and reverses hyperlocomotor activity in BDNF+/− mice. Moreover, inhibition of STEP61 by TC-2153 is sufficient to enhance the Tyr phosphorylation of STEP substrates and also reverses hyperlocomotion in BDNF+/− mice. These findings give us a better understanding of the regulation of STEP61 by BDNF in normal cognitive functions and in neuropsychiatric disorders.

    2. ADAM10 and BACE1 are localized to synaptic vesicles

      Jolanta L. Lundgren, Saheeb Ahmed, Sophia Schedin-Weiss, Gunnar K. Gouras, Bengt Winblad, Lars O. Tjernberg and Susanne Frykman

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13287

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      The amyloid-β (Aβ) precursor protein, FL-APP, is cleaved into the synaptotoxic Aβ by BACE1 and γ-secretase while ADAM10 cleavage precludes Aβ formation. We demonstrate enrichment of ADAM10 and BACE1, but not γ-secretase, in synaptic vesicles which indicates that the first step of APP processing occurs in synaptic vesicles whereas the final step is more likely to take place elsewhere.

    3. The neonicotinoid imidacloprid, and the pyrethroid deltamethrin, are antagonists of the insect Rdl GABA receptor

      Jennina Taylor-Wells, Basil D. Brooke, Isabel Bermudez and Andrew K. Jones

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13290

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      We show for the first time that deltamethrin (a pyrethroid insecticide) and imidacloprid (a neonicotinoid insecticide) act directly on the insect GABA receptor, Rdl. Our findings highlight Rdl as a potential secondary target of pyrethroids and neonicotinoids mutations in which may contribute to resistance to these widely used insecticides.

    4. Tph2 gene deletion enhances amphetamine-induced hypermotility: effect of 5-HT restoration and role of striatal noradrenaline release

      Mirjana Carli, Chrysaugi Kostoula, Giuseppina Sacchetti, Pierangela Mainolfi, Alessia Anastasia, Claudia Villani and Roberto William Invernizzi

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13280

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      Acute sensitivity to the motor effects of amphetamine has been associated to increased risk of psychostimulant abuse. Here, we show that deletion of Tph2, the gene responsible for brain 5-HT synthesis, enhances the motor effect of amphetamine in mice through the inhibition of striatal NA release. This suggests that Tph2−/− mice is a useful preclinical model to assess the role of 5-HT-dependent mechanisms in psychostimulants action. Tph2, tryptophan hydroxylase-2.

    5. Transplanted microvascular endothelial cells promote oligodendrocyte precursor cell survival in ischemic demyelinating lesions

      Keiya Iijima, Masashi Kurachi, Koji Shibasaki, Masae Naruse, Sandra Puentes, Hideaki Imai, Yuhei Yoshimoto, Masahiko Mikuni and Yasuki Ishizaki

      Article first published online: 17 SEP 2015 | DOI: 10.1111/jnc.13262

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      Transplanted microvascular endothelial cells (MVECs) release humoral factors which increase the number of oligodendrocyte precursor cells (OPCs) by inhibiting their apoptotic death. The resultant increase in OPCs promotes remyelination by existing (intrinsic) mature oligodendrocytes in the ischemic infarct region. Identification of such humoral factors may lead to the new therapeutic strategy against ischemic demyelinating diseases.

  11. Reviews

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      Stochastic optical reconstruction microscopy (STORM) in comparison with stimulated emission depletion (STED) and other imaging methods

      Johnny Tam and David Merino

      Article first published online: 14 SEP 2015 | DOI: 10.1111/jnc.13257

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      Stochastic optical reconstruction microscopy (STORM) and stimulated emission depletion (STED) are two super-resolution microscopy approaches that have rapidly gained popularity in recent years. STORM is based on the precise localization of a large number of individual molecules that together form a super-resolved image (bottom), whereas STED is based on the scanning of two super-imposed light sources which together allow for a super-resolved spot on the sample to be imaged (top). We discuss the specific advantages and disadvantages of each technique and explain the various parameters that affect image quality, which should be taken into consideration when planning experiments.

  12. Editorial Highlights

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      An integrated energy plan for activated neurons

      Leloup Corinne

      Article first published online: 14 SEP 2015 | DOI: 10.1111/jnc.13276

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      This Editorial highlights an ingenious study by Li and Freeman published in this issue of J. Neurochem. Accurately knowing the brain extracellular levels of the two main substrates, that is, glucose and lactate, while a well-controlled and graded-stimulus is applied, might be extremely useful to finely understand how these substrates are produced and used. To that end, the authors have designed a new approach that consists to record at the same time (100 ms resolution) extracellular glucose and lactate concentrations using electrochemical sensing microelectrodes equally distant from a microelectrode that registers the multicellular activity in response to light-dependent stimuli (contrast levels from 10% to 80%). While this approach does, however, not evaluate the metabolic coupling between astrocytes and neurons, it proposes a new design which combined with molecular strategies specifically toward the glial or neuronal compartments will certainly help to demonstrate new distinctive features of this interesting question.

      Read the full article ‘Neurometabolic coupling between neural activity, glucose, and lactate in activated visual cortex’ on doi: 10.1111/jnc.13143.

  13. Reviews

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      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.

  14. Short Communications

    1. Maturational alterations in constitutive activity of medial prefrontal cortex kappa-opioid receptors in Wistar rats

      Sunil Sirohi and Brendan M. Walker

      Article first published online: 11 SEP 2015 | DOI: 10.1111/jnc.13279

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      Opioid receptors exhibit agonist-independent constitutive activity; however, kappa-opioid receptor (KOR) constitutive activity has not been demonstrated in native systems. Our results confirm KOR constitutive activity in the medial prefrontal cortex (mPFC) that declines with age. With the ability to presynaptically inhibit multiple neurotransmitter systems in the mPFC, maturational or patho-logical alterations in constitutive activity could disrupt corticofugal glutamatergic pyramidal projection neurons mediating executive function. Regulation of KOR constitutive activity could serve as a therapeutic target to treat compromised executive function.

  15. Original Articles

    1. Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB1R signaling and anxiety-like behavior

      Roberta Imperatore, Giovanna Morello, Livio Luongo, Ulrike Taschler, Rosaria Romano, Danilo De Gregorio, Carmela Belardo, Sabatino Maione, Vincenzo Di Marzo and Luigia Cristino

      Article first published online: 11 SEP 2015 | DOI: 10.1111/jnc.13267

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      In this study, the authors provide evidence that congenitally enhanced endocannabinoid levels in the neuronal circuits underlying anxiety-like behavioral states (mainly medial prefrontal cortex, amygdala and hippocampus) lead to CB1R desenistization and anxiety and depression. MAGL−/− mice, a model of congenital overactivity of the eCB system, exhibited a compensatory impairment of CB1R signaling in anxiety-associated brain areas and a subsequent change in excitatory/inhibitory tone associated with altered score in the marble burying and light/dark box test, in concomitance with anxiety and depression behavior states. These findings may have potential relevance to the understanding of the neurochemical effects of chronic CB1R overstimulation in cannabis abusers.

    2. Neuronal acid-induced [Zn2+]i elevations calibrated using the low-affinity ratiometric probe FuraZin-1

      Lech Kiedrowski

      Article first published online: 10 SEP 2015 | DOI: 10.1111/jnc.13282

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      In vitro, upon acidification, Zn2+-cysteine complexes release Zn2+ and ATP chelates the released Zn2+. However, in vivo (cultured neurons), an ATP depletion failed to enhance acid-induced [Zn2+]i elevations. These [Zn2+]i elevations were calibrated using a low affinity ratiometric probe FuraZin-1; they reached 2 µM levels and increased to 5 µM when a thiol-reactive agent, N-ethylmaleimide, compromised Zn2+ binding by cysteines.

    3. TGR5 signaling reduces neuroinflammation during hepatic encephalopathy

      Matthew McMillin, Gabriel Frampton, Richard Tobin, Giuseppina Dusio, Jenny Smith, Hope Shin, Karen Newell-Rogers, Stephanie Grant and Sharon DeMorrow

      Article first published online: 10 SEP 2015 | DOI: 10.1111/jnc.13243

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      This study supports that betulinic acid infusion into the brain during hepatic encephalopathy reduces the release of the neuronal cytokine CCL2 and subsequently inhibits proinflammatory cytokine release from microglia. This improves neurological outcomes in a mouse model of hepatic encephalopathy and identifies a potential therapeutic target for management of this disease.

    4. You have full text access to this OnlineOpen article
      Neuronal connectivity between habenular glutamate-kisspeptin1 co-expressing neurons and the raphe 5-HT system

      Fatima M. Nathan, Satoshi Ogawa and Ishwar S. Parhar

      Article first published online: 10 SEP 2015 | DOI: 10.1111/jnc.13273

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      The neuropeptide kisspeptin (Kiss1) play a key role in vertebrate reproduction. We have previously shown modulatory role of habenular Kiss1 in the raphe serotonin (5-HT) systems. This study proposed that the habenular Kiss1 neurons modulate the 5-HT system primarily through glutamatergic neurotransmission, which provides an important insight for understanding of the modulation of 5-HT system by the habenula-raphe pathway.

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      Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8-deficient mice

      Kelly E. Bosse, Jennifer L. Charlton, Laura L. Susick, Brooke Newman, Andrew L. Eagle, Tiffany A. Mathews, Shane A. Perrine and Alana C. Conti

      Article first published online: 10 SEP 2015 | DOI: 10.1111/jnc.13235

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      Calcium/calmodulin-stimulated adenylyl cyclase (AC) isoforms 1 and 8 were studied for their involvement in the adaptive neurobehavioral responses to methamphetamine. AC 1/8 double knockout (DKO) mice showed heightened basal locomotor activity and dorsal striatal dopamine responsivity. Conversely, methamphetamine-induced locomotor activity was attenuated in DKO mice, accompanied by reductions in dopamine and HVA content and impaired DARPP-32 activation. These findings indicate AC 1/8 signaling regulates the sensitivity of the nigrostriatal pathway subserving stimulant and neuroadaptive sensitizing effects of methamphetamine. 3-MT, 3-methoxytyramine; Ca2+, calcium; CaM, calmodulin; cdk5; cyclin-dependent kinase 5; DA, dopamine; DARPP-32, dopamine- and cAMP-regulated phosphoprotein; D1R, dopamine D1 receptor; HVA, homovanillic acid; PKA, protein kinase A.

    6. Age-dependent loss of parvalbumin-expressing hippocampal interneurons in mice deficient in CHL1, a mental retardation and schizophrenia susceptibility gene

      Barbara Schmalbach, Eka Lepsveridze, Nevena Djogo, Giorgi Papashvili, Fang Kuang, Iryna Leshchyns'ka, Vladimir Sytnyk, Alexander G. Nikonenko, Alexander Dityatev, Igor Jakovcevski and Melitta Schachner

      Article first published online: 8 SEP 2015 | DOI: 10.1111/jnc.13284

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      Close homolog of L1-deficient (CHL1−/−) mice have abnormally high numbers of parvalbumin (PV)-expressing hippocampal interneurons in juvenile animals, but in adult animals a loss of these cells is observed. This loss correlates with an increased density of microglia (M), enhanced interleukin-6 (IL6) production and a deficit in short- and long-term potentiation at CA3–CA1 excitatory synapses. Furthermore, adult CHL1−/− mice display behavioral traits similar to those observed in neuropsychiatric disorders of humans.

  16. Letters to the Editor

    1. Are positive allosteric modulators of α7 nAChRs clinically safe?

      Victor Uteshev

      Article first published online: 8 SEP 2015 | DOI: 10.1111/jnc.13236

      A comment on “Positive allosteric modulation of alpha-7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum” by M. Cano-Abad et al. (2014) J Neurochem 133(3), 309–319 (DOI: 10.1111/jnc.13049).

  17. Original Articles

    1. You have full text access to this OnlineOpen article
      Norepinephrine and its metabolites are involved in the synthesis of neuromelanin derived from the locus coeruleus

      Kazumasa Wakamatsu, Keisuke Tabuchi, Makoto Ojika, Fabio A. Zucca, Luigi Zecca and Shosuke Ito

      Article first published online: 4 SEP 2015 | DOI: 10.1111/jnc.13237

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      Using the chemical degradation methods for the determination of catechols in neuromelanin (NM), we have shown that dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxyphenylethanol (DOPE), and 3,4-dihydroxyphenylalanine (DOPA) are mainly responsible for the structure of NM from substantia nigra (SN), while norepinephrine (NE), 3,4-dihydroxymandelic acid (DOMA), and 3,4-dihydroxyphenylethylene glycol (DOPEG) are additionally responsible for the structure of NM from locus coeruleus (LC).

  18. Reviews

    1. 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.

  19. Original Articles

    1. Multiple C2 domains transmembrane protein 1 is expressed in CNS neurons and possibly regulates cellular vesicle retrieval and oxidative stress

      Lifeng Qiu, Hanry Yu and Fengyi Liang

      Article first published online: 3 SEP 2015 | DOI: 10.1111/jnc.13251

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      MCTP1 in the CNS is a neuronal vesicle/endosome protein. Mutation or expression variation of MCTP1 has been associated with neuropsychiatric disorders. The present in vivo and in vitro imaging studies demonstrated vesicular localization of MCTP1 on the endocytic recycling pathway. Functional assays indicated involvement of MCTP1 in multiple cellular functions including endocytosis, cell migration and anti-excitotoxicity in neuronal cells.

  20. Reviews

    1. You have free access to this content
      Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders

      Carlo Sala, Cinzia Vicidomini, Ilaria Bigi, Adele Mossa and Chiara Verpelli

      Article first published online: 3 SEP 2015 | DOI: 10.1111/jnc.13232

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      Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia (SCZ). With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations.

  21. Short Communications

    1. Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke

      Fan Li, Joel Faustino, Moon-Sook Woo, Nikita Derugin and Zinaida S. Vexler

      Article first published online: 3 SEP 2015 | DOI: 10.1111/jnc.13239

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      Microglial cells contribute to acute and sub-chronic injury in adult stroke models, whereas in neonatal rodents they serve as endogenous neuroprotectants early following transient middle cerebral artery occlusion (tMCAO), limiting neuroinflammation and injury. In the neonate, microglial depletion or lack of the scavenger receptor CD36 exacerbates injury. In this study we asked if lack of CD36 affects microglial phenotypes after neonatal stroke. Expression of several pro-inflammatory genes, including Toll-like receptors (TLR), remains largely unaffected in activated microglia in injured regions. Lack of CD36 alters several functions of microglia in acutely injured neonatal brain: it affects, among others, protein expression of its co-receptor, TLR2, but does not affect accumulation of superoxide in microglia or the cytokines TNFα and IL-1β in injured regions. We propose that TLR2 function (2&3) in part depends on CD36 function (2).

  22. Original Articles

    1. Reduction in mRNA and protein expression of a nicotinic acetylcholine receptor α8 subunit is associated with resistance to imidacloprid in the brown planthopper, Nilaparvata lugens

      Yixi Zhang, Xin Wang, Baojun Yang, Yuanyuan Hu, Lixin Huang, Chris Bass and Zewen Liu

      Article first published online: 3 SEP 2015 | DOI: 10.1111/jnc.13281

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      In insects, target-site mutations often cause high resistance to insecticides, such as neonicotinoids acting on nicotinic acetylcholine receptors (nAChRs). Here we found that a quantitative change in target-protein level, decrease in mRNA and protein levels of Nlα8, contributed importantly to imidacloprid resistance in Nilaparvata lugens. This finding provides a new target-site mechanism of insecticide resistance.

    2. Regulation of NOD-like receptors and inflammasome activation in cerebral endothelial cells

      Péter Nagyőszi, Ádám Nyúl-Tóth, Csilla Fazakas, Imola Wilhelm, Mihály Kozma, Judit Molnár, János Haskó and István A. Krizbai

      Article first published online: 3 SEP 2015 | DOI: 10.1111/jnc.13197

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      Here, we show that cerebral endothelial cells (CECs), the main components of the blood–brain barrier, express several NOD (nucleotide-binding oligomerization domain-containing protein)-like receptors and are able to assemble functional inflammasomes. Expression of key inflammasome components (NOD2, NLRP3, and caspase 1) along with caspase-cleaved interleukins IL-1β and IL-33 can be induced in CECs by priming with lipopolysaccharide (LPS) and activation with muramyl dipeptide (MDP). Combined treatment with LPS and MDP results in IL-1β secretion in a caspase (i.e., inflammasome)- and ERK1/2-dependent manner.

    3. Laminin promotes metalloproteinase-mediated dystroglycan processing to regulate oligodendrocyte progenitor cell proliferation

      Cindy V. Leiton, Azeez Aranmolate, Christopher Eyermann, Michael J. Menezes, Luisa F. Escobar-Hoyos, Solomon Husain, Steve J. Winder and Holly Colognato

      Article first published online: 2 SEP 2015 | DOI: 10.1111/jnc.13241

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      A subset of dystroglycan expressed in oligodendrocyte progenitors is cleaved by (1) a metalloproteinase, and, predicted, (2) by a γ-secretase to generate an intracellular β−dystroglycan fragment. Cleavage occurs preferentially following attachment to the dystroglycan extracellular ligand, laminin-211. The intracellular portion of cleaved dystroglycan then promotes oligodendrocyte progenitor proliferation, providing a novel reciprocal mechanism by which laminin–dystroglycan interactions influence oligodendroglial development. MMP, matrix metalloproteinase.

    4. Resveratrol prevents cadmium activation of Erk1/2 and JNK pathways from neuronal cell death via protein phosphatases 2A and 5

      Chunxiao Liu, Ruijie Zhang, Chenxia Sun, Hai Zhang, Chong Xu, Wen Liu, Wei Gao, Shile Huang and Long Chen

      Article first published online: 2 SEP 2015 | DOI: 10.1111/jnc.13233

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      Resveratrol, a natural polyphenol compound, has been found to exert neuroprotective effects. This study uncovers that resveratrol prevents cadmium (Cd)-induced activation of Erk1/2 and JNK pathways and neuronal cell death via activating PP2A and PP5. The findings propose that resveratrol may serve as a potential therapeutic agent in the prevention of Cd-induced neurodegenerative diseases.

  23. Reviews

    1. You have free access to this content
      The pathogenic role of the inflammasome in neurodegenerative diseases

      Leslie C. Freeman and Jenny P.-Y. Ting

      Article first published online: 2 SEP 2015 | DOI: 10.1111/jnc.13217

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      We here review the role of the inflammasome in the pathogenesis of traumatic brain injury (TBI). TBI is initiated by physical force exerted to head, resulting in neuronal injury and death. Primary insult is followed by a secondary cascade of events following neuroinflammation such as mitochondrial dysfunction, production of reactive oxygen species, potassium effluxes, and release of circulating DNA. These events can potentially trigger the activation of NLRP3, NLRP1, and AIM2 during TBI but have yet to be confirmed (dashed lines). NLRP3, NLRP1, and AIM2 associate with the adaptor protein ASC, which initiates the cleavage of pro-caspase-1 to the mature form of caspase-1 which cleaves pro-IL-1β and pro-IL-18 into their mature forms of IL-1β and IL-18.

  24. Original Articles

    1. Treatment with human immunoglobulin G improves the early disease course in a mouse model of Duchenne muscular dystrophy

      Jana Zschüntzsch, Yaxin Zhang, Florian Klinker, Gregor Makosch, Lars Klinge, Dörthe Malzahn, Heinrich Brinkmeier, David Liebetanz and Jens Schmidt

      Article first published online: 28 AUG 2015 | DOI: 10.1111/jnc.13269

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      Two monthly intraperitoneal injections of human immunoglobulin G (IgG) improved the early 11-week disease phase of mdx mice. Voluntary running was improved and serum levels of creatine kinase were diminished. In the skeletal muscle, myopathic damage was ameliorated and key inflammatory markers such as mRNA expression of SPP1 and infiltration by macrophages were reduced. The study suggests that IgG could be explored as a potential treatment option for Duchenne muscular dystrophy and that pre-clinical long-term studies should be helpful.

    2. Differential peptidomics assessment of strain and age differences in mice in response to acute cocaine administration

      Elena V. Romanova, Stanislav S. Rubakhin, John R. Ossyra, Jonathan A. Zombeck, Michael R. Nosek, Jonathan V. Sweedler and Justin S. Rhodes

      Article first published online: 25 AUG 2015 | DOI: 10.1111/jnc.13265

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      Peptides were measured using mass spectrometry (MALDI-TOF) in individual lateral hypothalamus and pituitary samples from four strains and two ages of inbred mice in response to acute cocaine administration. Principal component analyses (PCA) classified the strains according to their peptide profiles from adolescent mice, and a subset of peptides in the lateral hypothalamus was altered by cocaine in adolescents.

    3. Serotonergic dysfunction in the A53T alpha-synuclein mouse model of Parkinson's disease

      Janina Deusser, Stefanie Schmidt, Benjamin Ettle, Sonja Plötz, Sabine Huber, Christian P. Müller, Eliezer Masliah, Jürgen Winkler and Zacharias Kohl

      Article first published online: 25 AUG 2015 | DOI: 10.1111/jnc.13253

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      A transgenic mouse model of Parkinson's disease (PD) shows α-synuclein expression in serotonergic neurons of raphe nuclei. Besides lower serotonin levels in the raphe nuclei, a topographical restricted reduction in serotonergic fiber density was present in the hippocampus accompanied by an impaired fluoxetine-response of hippocampal neuroblasts. In conclusion, α-synuclein in the serotonergic system may account for psychiatric symptoms in PD. DR, dorsal raphe nucleus; MnR, median raphe nucleus.

    4. Up-regulation of c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) contributes to BDNF-enhanced neurotransmitter release

      Bing Chen, Xin-Liang Ma, Zhao Geng, Shu-Hong Huang, Lu-Kai Zhai, Yun-Yun Guo and Zhe-Yu Chen

      Article first published online: 25 AUG 2015 | DOI: 10.1111/jnc.13226

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      We demonstrated that in hippocampal neurons BDNF/TrkB signaling mediates transcriptional up-regulation of c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) via CREB activation. The up-regulation of JIP3 further contributes to BDNF-enhanced neurotransmitter release. These findings provide insight into the mechanistic link between BDNF-mediated gene expression and its more sustained pre-synaptic modulation, which may help us to further understand the roles of BDNF in neuronal plasticity.

    5. Live imaging of endogenous Ca2+/calmodulin-dependent protein kinase II in neurons reveals that ischemia-related aggregation does not require kinase activity

      Kelsey Barcomb, Dayton J. Goodell, Don B. Arnold and K. Ulrich Bayer

      Article first published online: 25 AUG 2015 | DOI: 10.1111/jnc.13263

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      CaMKII aggregation is prevented by inhibiting kinase activity with mutations (red italics; shown previously) or inhibitors (red bold; shown here), indicating requirement of kinase activity. However, we show here that nucleotide-competitive inhibitors (green) allow CaMKII aggregation (including endogenous CaMKII within neurons), demonstrating that kinase activity is not required and supporting the current mechanistic model for CaMKII aggregation.

    6. Calcitonin gene-related peptide erases the fear memory and facilitates long-term potentiation in the central nucleus of the amygdala in rats

      Xin Wu, Jie-Ting Zhang, Jue Liu, Si Yang, Tao Chen, Jian-Guo Chen and Fang Wang

      Article first published online: 18 AUG 2015 | DOI: 10.1111/jnc.13246

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      Calcitonin gene-related peptide (CGRP) plays an essential role in synaptic plasticity in the amygdala and fear memory. We found that CGRP-induced chemical long-term potentiation (LTP) in a dose-dependent way in the BLA–CeA (basolateral and central nucleus of amygdala, respectively) pathway and enhanced fear memory extinction in rats through a protein kinase A (PKA)-dependent postsynaptic mechanism that involved NMDA receptors. These results support a pivotal role of CGRP in amygdala.

    7. DISC1 regulates expression of the neurotrophin VGF through the PI3K/AKT/CREB pathway

      Carmen Rodríguez-Seoane, Adriana Ramos, Carsten Korth and Jesús R. Requena

      Article first published online: 12 AUG 2015 | DOI: 10.1111/jnc.13258

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      Our data show that DISC1 regulates the activation state of the PI3K/AKT/CREB signaling route and in turn, contributes to regulate the expression of the neuropeptide precursor VGF in neurons. DISC1 might modulate this molecular pathway by regulating the localization of Grb2 in the cell that promotes the activation of PI3K. Given the important roles of VGF in mental disease, the DISC1-VGF connection might prove to be important for efforts to develop new therapies for these devastating diseases.

    8. 2, 2′- and 4, 4′-Cyanines are transporter-independent in vitro dopaminergic toxins with the specificity and mechanism of toxicity similar to MPP+

      Chamila C. Kadigamuwa, Viet Q. Le and Kandatege Wimalasena

      Article first published online: 12 AUG 2015 | DOI: 10.1111/jnc.13201

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      Here, we show that cationic lipophilic cyanines with structural similarity to 1-methyl-4-phenylpyridinium (MPP+) freely accumulate non-specifically, but only toxic to dopaminergic cells. They are 1000-fold more toxic than MPP+ under similar conditions. They cause mitochondrial depolarization non-specifically, but increase the ROS specifically in dopaminergic cells leading to the apoptotic cell death parallel to MPP+. Thus, the specific dopaminergic toxicity of MPP+ and related toxins could be due to the intrinsic vulnerability of dopaminergic cells toward mitochondrial oxidative stress.

    9. Ethanol activates midkine and anaplastic lymphoma kinase signaling in neuroblastoma cells and in the brain

      Donghong He, Hu Chen, Hisako Muramatsu and Amy W. Lasek

      Article first published online: 11 AUG 2015 | DOI: 10.1111/jnc.13252

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      We propose that ethanol (a) increases transcription of the anaplastic lymphoma kinase (ALK) and midkine (MDK) genes and (b) rapidly activates extracellular signal-regulated kinase (pERK1/2) and signal transducer and activator of transcription 3 (pSTAT3) through MDK and ALK. Activation of ALK and MDK signaling by ethanol may alter behavioral responses to ethanol with implications for the development of alcohol use disorders.

    10. Pinnatoxins E, F and G target multiple nicotinic receptor subtypes

      Shane D. Hellyer, Dinesh Indurthi, Thomas Balle, Vanda Runder-Varga, Andrew I. Selwood, Joel D.A. Tyndall, Mary Chebib, Lesley Rhodes and D. Steven Kerr

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13245

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      We used a three-pronged approach of radioligand binding, electrophysiological recording and molecular modelling to determine the nicotinic antagonist properties of the marine algal pinnatoxins E, F and G. These high-affinity toxins bind to and antagonize muscle nicotinic receptors, as well as homomeric and heteromeric neuronal nicotinic receptors, and show a preference for homomeric neuronal and muscle-type receptors over heteromeric neuronal receptors. Modelling of pinnatoxin/receptor interactions revealed potential determinants for binding to each of the receptor subtypes. This high-affinity nicotinic binding presumably underlies the neuromuscular and CNS symptoms associated with pinnatoxin intoxication.

  25. Editorial Highlights

    1. You have free access to this content
      Are GLP-1 receptor agonists useful against traumatic brain injury?

      Colin K. Combs

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13224

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      This Editorial highlights a study by Li et al. (2015) in the current issue of J. Neurochem. The image depicts the hypothesized neuroprotective pathway that is proposed by the authors. Using a combination of SH-SY5Y and primary rat neuron cultures the GLP-1R agonist, Liraglutide, was shown to increase SH-SY5Y proliferation and CREB phosphorylation correlating with reduced toxicity, preservation of Bcl2 protein levels, and decreased caspase 3 activity following glutamate or H2O2 stimulations. These in vitro observations correlated with a Liraglutide-dependent improvement in memory performance in mice subjected to a mild TBI. Bcl2, B-cell lymphoma 2; CREB, cAMP-response element binding protein; GLP-1R, glucagon-like peptide 1 receptor; TBI, traumatic brain injury; PKA, protein kinase A.

      Read the full article ‘Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice’ on doi: 10.1111/jnc.13169.

  26. Original Articles

    1. Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice

      Yazhou Li, Miaad Bader, Ian Tamargo, Vardit Rubovitch, David Tweedie, Chaim G. Pick and Nigel H. Greig

      Article first published online: 18 JUN 2015 | DOI: 10.1111/jnc.13169

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      Exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of traumatic brain injury (TBI). Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pretreatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro, likely involving the cAMP/PKA/pCREB pathway. Our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI.

  27. Reviews

    1. You have full text access to this OnlineOpen article
      Immune dysfunction in Niemann-Pick disease type C

      Nick Platt, Annelise O. Speak, Alexandria Colaco, James Gray, David A. Smith, Ian M. Williams, Kerri-Lee Wallom and Frances M. Platt

      Article first published online: 4 JUN 2015 | DOI: 10.1111/jnc.13138

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      Niemann-Pick disease type C is a rare, devastating, inherited lysosomal storage disease with a unique cellular phenotype characterized by lysosomal accumulation of sphingosine, various glycosphingolipids and cholesterol and a reduction in lysosomal calcium. In this review we highlight the impact of the disease on innate immune activities in both the central nervous system (CNS) and peripheral tissues and discuss their contributions to pathology and the underlying mechanisms.

  28. Original Articles

    1. Neurometabolic coupling between neural activity, glucose, and lactate in activated visual cortex

      Baowang Li and Ralph D. Freeman

      Article first published online: 29 MAY 2015 | DOI: 10.1111/jnc.13143

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      Dynamic changes in energy metabolites can be measured directly with high spatial and temporal resolution by use of enzyme-based microelectrodes. Here, to examine neuro-metabolic coupling during brain activation, we use combined microelectrodes to simultaneously measure extracellular glucose, lactate, and neural responses in the primary visual cortex to visual stimulation. We demonstrate rapid decreases in glucose and increases in lactate during neural activation. Changes in glucose and lactate signals are transient and closely coupled with neuronal firing.

    2. Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors

      Siddhartha Dalvi, Hieu H. Nguyen, Ngoc On, Ryan W. Mitchell, Harold M. Aukema, Donald W. Miller and Grant M. Hatch

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13117

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      The blood–brain barrier, formed by microvessel endothelial cells, is a restrictive barrier between the brain parenchyma and the circulating blood. Radiolabeled arachidonic acid (ARA) movement across, and monolayer permeability in the presence of ARA, was examined in confluent monolayers of primary human brain microvessel endothelial cells (HBMECs) cultured on Transwell® plates. Incubation of HBMECs with ARA resulted in a rapid increase in HBMEC monolayer permeability. The mechanism was mediated, in part, through increased prostaglandin E2 production from ARA which acted upon EP3 and EP4 receptors to increase HBMEC monolayer permeability.

    3. Recombinant adeno-associated viral (rAAV) vectors mediate efficient gene transduction in cultured neonatal and adult microglia

      Wei Su, John Kang, Bryce Sopher, James Gillespie, Macarena S. Aloi, Guy L. Odom, Stephanie Hopkins, Amanda Case, David B. Wang, Jeffrey S. Chamberlain and Gwenn A. Garden

      Article first published online: 20 MAR 2015 | DOI: 10.1111/jnc.13081

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      Neonatal microglia are functionally distinct from adult microglia, although the majority of in vitro studies utilize rodent neonatal microglia cultures because of difficulties of culturing adult cells. In addition, cultured microglia are refractory to most methods for modifying gene expression. Here, we developed a novel protocol for culturing adult microglia and evaluated the feasibility and efficiency of utilizing Recombinant Adeno-Associated Virus (rAAV) to modulate gene expression in cultured microglia.

  29. Reviews

    1. You have free access to this content
      Microglia and neuroprotection

      Zhihong Chen and Bruce D. Trapp

      Article first published online: 10 MAR 2015 | DOI: 10.1111/jnc.13062

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      Microglia are the resident innate immune cells of the CNS. Despite the traditional view of microglia as being destructive in neurological diseases, recent studies have shown that they maintain tissue homeostasis and protect the CNS under various pathological conditions. They achieve so by clearing debris, promoting neurogenesis, suppressing inflammation and stripping inhibitory synapses. This review summarizes recent advances of our understanding on the multi-dimensional neuroprotective roles of microglia.

  30. Original Articles

    1. Exosome-mediated inflammasome signaling after central nervous system injury

      Juan Pablo de Rivero Vaccari, Frank Brand III, Stephanie Adamczak, Stephanie W. Lee, Jon Perez-Barcena, Michael Y. Wang, M. Ross Bullock, W. Dalton Dietrich and Robert W. Keane

      Article first published online: 1 MAR 2015 | DOI: 10.1111/jnc.13036

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      We propose the following signaling cascade for inflammasome activation in peripheral tissues after CNS injury: CNS trauma induces inflammasome activation in the nervous system and secretion of exosomes containing inflammasome protein cargo into cerebral spinal fluid. The inflammasome containing exosomes then fuse with target cells to activate the innate immune response in peripheral tissues. We suggest that these findings may be used to develop new therapeutics to treat the devastating inflammation and cell destruction evoked by CNS injuries. IL-1β and IL-18 = pro-inflammatory cytokines.


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