Journal of Neurochemistry

Cover image for Vol. 134 Issue 5

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

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  1. 1 - 58
  1. Short Communications

    1. The tumor suppressor p53 guides GluA1 homeostasis through Nedd4-2 during chronic elevation of neuronal activity

      Kathryn A. Jewett, Jiuhe Zhu and Nien-Pei Tsai

      Article first published online: 27 AUG 2015 | DOI: 10.1111/jnc.13271

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      Chronic neuronal activity perturbation triggers homeostatic mechanisms at the synapses. We reported that the tumor suppressor p53 and its modulator Mdm2 guide the ubiquitination and down-regulation of the GluA1 subunit of AMPA receptor during activity stimulation. Nedd4-2, a direct target of p53, is identified as a new ubiquitin E3 ligase for GluA1, providing a novel mechanism to fine-tune post-synaptic homeostasis.

  2. Original Articles

    1. Insulin receptor A and Sirtuin 1 synergistically improve learning and spatial memory following chronic salidroside treatment during hypoxia

      Kalpana Barhwal, Saroj K. Das, Ashish Kumar, Sunil K. Hota and Ravi B. Srivastava

      Article first published online: 27 AUG 2015 | DOI: 10.1111/jnc.13225

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      We propose a novel mechanism for salidroside-mediated neuroprotection in hypoxia. Salidroside phosphorylates and activates Insulin Receptor A subunit which in turn leads to phosphorylation of Akt and ERK and subsequent activation of AMPK (AMP-activated protein kinase). Salidroside also increases Sirt1 activity which along with pAMPK mediates mitochondrial biogenesis.

  3. Short Communications

    1. You have full text access to this OnlineOpen article
      Identification of key amino acids responsible for the distinct aggregation properties of microtubule-associated protein 2 and tau

      Ce Xie, Yoshiyuki Soeda, Yuki Shinzaki, Yasuko In, Koji Tomoo, Yasuo Ihara and Tomohiro Miyasaka

      Article first published online: 26 AUG 2015 | DOI: 10.1111/jnc.13228

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      Tau and microtubule-associated protein 2 (MAP2) are homologous microtubule-associated proteins in neurons. So far, it is largely unknown why tau but not MAP2 is selectively involved in the filamentous inclusions (neurofibrillary tangles, NFT) formation in tauopathies, including Alzheimer's disease. In this study, we found that the difference of only two amino acids in tau and MAP2 sequences may determine their different fates in tauopathies. These results may lead to the elucidation of tau deregulation in pathological conditions.

  4. Original Articles

    1. SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport

      Guido Hermey, Nadine Schmidt, Björn Bluhm, Daniel Mensching, Kristina Ostermann, Carsten Rupp, Dietmar Kuhl and Stefan Kins

      Article first published online: 26 AUG 2015 | DOI: 10.1111/jnc.13221

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      Altered APP trafficking is thought to modulate its processing. SorCS1 has been suggested to function in APP trafficking. We analyzed if the two SorCS1 variants, SorCS1b and SorCS1c, tie APP to the cell surface or modify its internalization and intracellular targeting. We observed co-localization and vesicular co-transport of APP and SorCS1, but independent internalization and sorting through a common post-endocytic pathway. Co-expression of one variant, SorCS1c, reduced anterograde APP transport. These data demonstrate that SorCS1 and APP share trafficking pathways and that SorCS1c can retain APP from insertion into anterograde transport vesicles.

    2. miR-144-3p exerts anti-tumor effects in glioblastoma by targeting c-Met

      Fengming Lan, Huiming Yu, Man Hu, Tingyi Xia and Xiao Yue

      Article first published online: 26 AUG 2015 | DOI: 10.1111/jnc.13272

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      We propose that the microRNA miR-144-3p plays an essential anti-tumor role in glioblastoma. A newly identified miR-144-3p/MET signaling axis could represent a novel target for cellular resistance to cancer therapeutic drugs and radiation in glioblastoma patients. Jak, janus kinase; Grb2, Growth factor receptor-bound protein 2; HGF; miR, microRNA; PI3K, phosphoinositol-3-kinase; Raf, rapidly accelerated fibrosarcoma; STAT, Signal Transducers and Activators of Transcription.

    3. 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.

    4. Elevated dopamine concentration in light-adapted zebrafish retinas is correlated with increased dopamine synthesis and metabolism

      Victoria P. Connaughton, Bradley Wetzell, Lynne S. Arneson, Vittoria DeLucia and Anthony L. Riley

      Article first published online: 25 AUG 2015 | DOI: 10.1111/jnc.13264

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      Dopamine concentration is elevated in lighted-adapted zebrafish retinas. This increase is correlated with an increase in both tyrosine hydroxylase (TH) and DOPAC (3,4-dihydroxyphenylacetic acid), suggesting that changes in dopamine concentration are due to light-adaptive changes in the synthesis, release and metabolism of dopamine. This is applicable to studies examining retinal mutants, the role of dopamine in disease or visual system development.

    5. 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.

    6. Extended conformation of the proline-rich domain of human aryl hydrocarbon receptor-interacting protein-like 1: implications for retina disease

      Ravi P Yadav, Anurima Majumder, Lokesh Gakhar and Nikolai O. Artemyev

      Article first published online: 25 AUG 2015 | DOI: 10.1111/jnc.13223

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      Mutations in the proline-rich domain (PRD) of human AIPL1 cause severe retinal diseases, yet the role of PRD and the mechanisms of PRD mutations are unknown. Here, we describe a SAXS-derived solution structure of AIPL1 and functional properties of disease-linked AIPL1-PRD mutants. This structure and functional analyses provide a framework for understanding the mechanisms of PRD in disease.

    7. 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.

    8. 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.

    9. Corticotropin releasing factor up-regulates the expression and function of norepinephrine transporter in SK-N-BE (2) M17 cells

      Jingjing Huang, Turan Tufan, Maoxian Deng, Gary Wright and Meng-Yang Zhu

      Article first published online: 18 AUG 2015 | DOI: 10.1111/jnc.13268

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      This study demonstrated that corticotropin release factor (CRF) up-regulated the expression and function of norepinephrine transporter (NET) in a concentration- and time-dependent manner, through activation of CRF receptors and possible histone acetylation in NET promoter. The results indicate that their interaction may play an important role in stress-related physiological and pathological status.

    10. 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.

  5. Reviews

    1. You have free access to this content
      Current approaches to enhance glutamate transporter function and expression

      Andréia C. K. Fontana

      Article first published online: 14 AUG 2015 | DOI: 10.1111/jnc.13200

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      Termination of glutamate neurotransmission by glutamate transporter EAAT2 is essential to maintain homeostasis in the brain and to avoid excitotoxicity. Dysfunction of EAAT2 has been correlated with various neurological pathologies. Therefore, activators of the function or enhancers of the expression of EAAT2 (green arrows) could serve as a potential therapy for these conditions. This review describes the current status of the search for EAAT2 activators and addresses challenges and limitations of this approach.

  6. Original Articles

    1. Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

      Holly C. Hunsberger, Daniel S. Weitzner, Carolyn C. Rudy, James E. Hickman, Eric M. Libell, Rebecca R. Speer, Greg A. Gerhardt and Miranda N. Reed

      Article first published online: 13 AUG 2015 | DOI: 10.1111/jnc.13230

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      TauP301L mice exhibit increased glutamate release and decreased glutamate clearance, leading to increased extracellular glutamate and excitotoxicity. Riluzole treatment reduced glutamate release and increased glutamate clearance. Improved glutamate regulation was associated with improvements in learning and memory, an increase in PSD95 expression, and a decrease in tau pathology in riluzole-treated TauP301L mice.

    2. 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.

    3. Mitochondrial impairment and oxidative stress compromise autophagosomal degradation of α-synuclein in oligodendroglial cells

      Katharina Pukaß, Olaf Goldbaum and Christiane Richter-Landsberg

      Article first published online: 12 AUG 2015 | DOI: 10.1111/jnc.13256

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      Glial cytoplasmic inclusions are characteristically observed in multiple system atrophy, their occurrence might be related to failure in protein degradation systems. Here, we show that in oligodendrocytes autophagy is the major route of α-synuclein degradation which is either endogenously expressed or added exogenously (1, 2). Mitochondrial impairment (3) disturbs the autophagic flux and leads to the accumulation of exogenously applied α-synuclein, and enhances its propensity to form aggregates intracellulary (4).

    4. 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.

    5. 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.

    6. Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice

      De-Lin Ma, Fu-Qiong Chen, Wei-Jie Xu, Wen-Zhu Yue, Gang Yuan and Yan Yang

      Article first published online: 11 AUG 2015 | DOI: 10.1111/jnc.13248

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      We found that liraglutide, a GLP-1 (glucagon-like peptide-1) analog, prevented the age-dependent Alzheimer-like tau hyperphosphorylation in diabetic db/db mice. We proposed that liraglutide crosses the blood–brain barrier, and binds GLP-1 receptors from which G beta gamma dissociates intracellularly to activate PI3K, resulting in activation of Akt, which suppress GSK-3β (glycogen synthase kinase-3β), and thereby prevents it from phosphorylating tau. IRS-1: insulin receptor substrate 1; IRS-2: insulin receptor substrate 2; PI3K: phosphatidylinositol 3-kinase.

    7. Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage

      Junli Liu, Daishi Tian, Madhuvika Murugan, Ukpong B. Eyo, Cheryl F. Dreyfus, Wei Wang and Long-Jun Wu

      Article first published online: 11 AUG 2015 | DOI: 10.1111/jnc.13242

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      Hv1 proton channel is required for cuprizone-induced microglial activation and ROS production. Mice lacking Hv1(Hv1−/−) have reduced ROS production, increased oligodendrocyte progenitor (NG2) proliferation, and are partially protected from demyelinatioin and motor deficits that follow curpizone exposure. These results suggest that Hv1 proton channel is a unique target for controlling NOX-dependent ROS production in the pathogenesis of multiple sclerosis.

    8. Heterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency

      Isabell Lebkuechner, Ulrika Wilhelmsson, Elin Möllerström, Marcela Pekna and Milos Pekny

      Article first published online: 10 AUG 2015 | DOI: 10.1111/jnc.13213

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      We previously demonstrated that Notch signaling from astrocytes to neural stem cells, that inhibits neurogenesis, depends on the intermediate filament (nanofilament) system of astrocytes. Here we report the existence of four subpopulations of astrocytes with respect to their Notch signaling competence. We show that the fraction of astrocytes that are Notch signaling incompetent increases after brain injury and corresponds to the fraction of Notch signaling incompetent astrocytes in primary astrocyte cultures. We also demonstrate that the subpopulation of Notch signal sending competent astrocytes decreases when their intermediate filament system is genetically ablated.

    9. Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation

      Li-Hua Sun, Tao Ban, Cheng-Di Liu, Qing-Xin Chen, Xu Wang, Mei-Ling Yan, Xue-Ling Hu, Xiao-Lin Su, Ya-Nan Bao, Lin-Lin Sun, Lin-Jing Zhao, Shuang-Chao Pei, Xue-Mei Jiang, De-Kang Zong and Jing Ai

      Article first published online: 7 AUG 2015 | DOI: 10.1111/jnc.13212

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      Schematic diagram of miR-195 mediated Aβ aggregation and tau hyperphosphorylation in chronic brain hypoperfusion (CBH). First, CBH results in the elevation of nuclear factor-κB (NF-κB), which binds with the promoter sequences of miR-195 and negatively regulates the expression of miR-195. Second, down-regulated miR-195 induces up-regulation of APP and BACE1 and leads to an increase in Aβ levels. Third, some of the elevated Aβ then enter the intracellular space and activate calpain, which promotes the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IκB; IκB is an inhibitor of NF-κB, which activates NF-κB. Cdk5/p25 directly phosphorylates Tau. Fourth, down-regulated miR-195 induces an up-regulation of p35, which provides the active substrates of p25. Our findings demonstrated that the down-regulation of miR-195 plays a key role in the increased vulnerability to dementia via the regulation of multiple targets following CBH.

    10. Fibroblast growth factor 2 mRNA expression evoked by amitriptyline involves extracellular signal-regulated kinase-dependent early growth response 1 production in rat primary cultured astrocytes

      Naoto Kajitani, Kazue Hisaoka-Nakashima, Mami Okada-Tsuchioka, Mayu Hosoi, Toshiki Yokoe, Norimitsu Morioka, Yoshihiro Nakata and Minoru Takebayashi

      Article first published online: 6 AUG 2015 | DOI: 10.1111/jnc.13247

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      Recent studies suggest that fibroblast growth factor 2 (FGF2) is involved in the antidepressant effect in the model of depression. The production of ERK-dependent early growth response 1 (EGR1) is a crucial part of the amitriptyline-induced FGF2 expression signaling cascade in rat primary cultured astrocytes. The findings elaborate an astrocytic mechanism that could be used to develop antidepressants.

    11. The mitochondrial uncoupling protein-2 is a master regulator of both M1 and M2 microglial responses

      Roberta De Simone, Maria Antonietta Ajmone-Cat, Manuela Pandolfi, Antonietta Bernardo, Chiara De Nuccio, Luisa Minghetti and Sergio Visentin

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13244

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      We show that the mitochondrial uncoupling protein-2 (UCP2) is central to the process of microglial activation, with opposite regulation of M1 and M2 responses. In UCP2-silenced microglia, lipopolysaccharide (LPS) triggers an enhanced inflammatory response characterized by a greater expression of M1 genes, whereas interleukin-4 (IL-4) fails in inducing M2 genes and reducing M1 genes. We propose UCP2 manipulation as a potential strategy for redirecting microglial response towards protective phenotypes.

    12. 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.

    13. Headless Myo10 is a regulator of microtubule stability during neuronal development

      Huali Yu, Dong Sun, Nannan Wang, Min Wang, Yongsheng Lan, Wenqiang Fan, Yang Zhao, Weixiang Guo and Xiaojuan Zhu

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13238

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      In this study, we demonstrate that headless myosin X (hMyo10) is involved in microtubule stability regulation, which is important for neuronal morphogenesis and migration. In vitro studies reveal that hMyo10 regulates Tau-1 positive axon formation through stabilizing microtubules. Furthermore, in vivo studies reveal that hMyo10-mediated microtubule stability has a profound effect on radial cortical neuronal migration and apical dendritic arborization.

    14. Serum paraoxonase and arylesterase activities of paraoxonase-1 (PON-1), mild cognitive impairment, and 2-year conversion to dementia: A pilot study

      Carlo Cervellati, Alessandro Trentini, Arianna Romani, Tiziana Bellini, Cristina Bosi, Beatrice Ortolani, Amedeo Zurlo, Angelina Passaro, Davide Seripa and Giovanni Zuliani

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13240

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      Our study showed that in patients with mild cognitive impairment (MCI) low serum levels of paraoxonase-1 (PON-1) activity is associated with a higher likelihood of developing Vascular Dementia, but not Alzheimer's Disease. The observed connection might be explained by the ability of PON-1 to retard low-density lipoprotein (LDL) oxidation, decrease oxidative stress, attenuate inflammation, and increase cholesterol efflux.

  7. Reviews

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      The phosphorylation of α-synuclein: development and implication for the mechanism and therapy of the Parkinson's disease

      Yan Xu, Yulin Deng and Hong Qing

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13234

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      The milestone study on the phosphorylation of α-synuclein mainly at Ser129, Ser87, and Tyr125 relating to PD in recent years as well as some clinical application exploration are overviewed. The potential pathways of the phosphorylated α-synuclein related to PD are also summarized. The review may supply more ideas and thinking on this issue for the scientists in related research field.

  8. Original Articles

    1. Intracellular levels of glutamate in swollen astrocytes are preserved via neurotransmitter reuptake and de novo synthesis: implications for hyponatremia

      Alexandra L. Schober and Alexander A. Mongin

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13229

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      We identified mechanisms that allow astrocytes to conserve intracellular l-glutamate (Glu) upon exposure to hypo-osmotic environment. Cell swelling activates volume-regulated anion channel (VRAC) and triggers loss of Glu, taurine (Tau), and other cytosolic amino acids. Glu is conserved via reuptake by Na+-dependent transporters and de novo synthesis in the reactions of mitochondrial transamination (TA). These findings explain why, in acute hyponatremia, extracellular levels of Tau can be dramatically elevated with minimal changes in extracellular Glu.

  9. Editorial Highlights

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      USP46: a new piece of the memory puzzle?

      Felipe C. Ribeiro, Luis E. Santos and Sergio T. Ferreira

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13227

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      Long-term potentiation (LTP) and long-term depression (LTD) are crucial for synaptic plasticity, and are driven by AMPA receptor (AMPAR) trafficking. Recent findings indicate that the ubiquitin–proteasome system, the main protein degradation machinery of the cell, plays a significant role in memory formation by regulating the induction and maintenance of LTP. Although previously suggested as a possibility, deubiquitination of mammalian AMPARs had not been demonstrated, and the search for an enzyme that mediates the processes continued. This Editorial Highlight discusses the relevance of a study published in the current issue of Journal of Neurochemistry, in which the authors Huo and collaborators now identified ubiquitin-specific peptidase 46 (USP46) as a specific AMPAR deubiquitinase.

      Read the full article ‘The deubiquitinating enzyme USP46 regulates AMPA receptor ubiquitination and trafficking’ on page doi: 10.1111/jnc.13194.

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      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.

  10. Original Articles

    1. Chemogenetic ablation of dopaminergic neurons leads to transient locomotor impairments in zebrafish larvae

      Rafael Godoy, Sandra Noble, Kevin Yoon, Hymie Anisman and Marc Ekker

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13214

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      We have generated transgenic zebrafish expressing nitroreductase for the conditional and specific ablation of dopaminergic (DA) neurons in the larval zebrafish brain. We are able to induce a persistent reduction in DA neurons with transient locomotor impairments. Our transgenic zebrafish offer a model for understanding the impact of altered DA neuron populations on larval locomotor function and for the study of dopamine neuron regeneration following tissue specific ablation.

  11. Reviews

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      Time and space profiling of NMDA receptor co-agonist functions

      Jean-Pierre Mothet, Matildé Le Bail and Jean-Marie Billard

      Article first published online: 3 AUG 2015 | DOI: 10.1111/jnc.13204

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      The N-Methyl D-Aspartic acid (NMDA) subtype of glutamate receptors are central to many physiological functions and are linked to brain disorders. Their functions require glutamate and a co-agonist d-serine or glycine. After years of intense research and controversy on the identity of the amino acid that serves as the right co-agonist, we are just entering a new era of consensus where glycine and d-serine are teaming up to regulate the function of different subsets of NMDA receptors and at different synapses during different time windows of brain development.

  12. Original Articles

    1. Tesmilifene modifies brain endothelial functions and opens the blood–brain/blood–glioma barrier

      Fruzsina R. Walter, Szilvia Veszelka, Mária Pásztói, Zoltán A. Péterfi, András Tóth, Gábor Rákhely, László Cervenak, Csongor S. Ábrahám and Mária A. Deli

      Article first published online: 23 JUL 2015 | DOI: 10.1111/jnc.13207

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      Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood–brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood–brain barrier functions, which may have therapeutic relevance.

    2. Mutual induction of transcription factor PPARγ and microRNAs miR-145 and miR-329

      Ashutosh Dharap, Courtney Pokrzywa, Shruthi Murali, Balarama Kaimal and Raghu Vemuganti

      Article first published online: 23 JUL 2015 | DOI: 10.1111/jnc.13220

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      We proposed that promoters of many microRNAs contain the binding sites for the transcription factor PPARγ. Activation of PPARγ modulates the expression of these microRNAs. Two such PPARγ-responsive microRNAs (miR-145 and miR-329) bind to PPARγ promoter to induce its expression. This indicates the presence of a feedback loop by which transcription factors and microRNAs can modulate each other.

    3. Glucose is a positive modulator for the activation of human recombinant glycine receptors

      Ulrike Breitinger, Karim M. Raafat and Hans-Georg Breitinger

      Article first published online: 23 JUL 2015 | DOI: 10.1111/jnc.13215

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      Glucose and related sugars are essential metabolites. We identified glucose and fructose as positive modulators of the human inhibitory glycine receptor, a neuronal ligand-gated ion channel. Receptor-mediated currents were enhanced at physiological concentrations (~ 10 mM of sugar). Direct modulation of a synaptic receptor by glucose is relevant in clinical cases of elevated blood glucose, and may be considered in experimental protocols.

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      Mu opioid receptor activation enhances regulator of G protein signaling 4 association with the mu opioid receptor/G protein complex in a GTP-dependent manner

      Rema Santhappan, Alicia Tamara Crowder, Shawn Gouty, Brian M. Cox and Thomas E. Côté

      Article first published online: 16 JUL 2015 | DOI: 10.1111/jnc.13222

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      Regulators of G protein Signaling (RGS) shorten the time that G proteins are active. Activation of the mu opioid receptor (MOR) causes GTP to bind to and to activate Go (αoβγ). RGS4 then binds to the activated αo-GTP/MOR complex and accelerates the intrinsic GTPase of αo. After αo dissociates from MOR, RGS4 remains bound to the C-terminal region of MOR.

    5. Dickkopf-related protein 3 is a potential Aβ-associated protein in Alzheimer's Disease

      Kim A. Bruggink, H. Bea Kuiperij, Jolein Gloerich, Irene Otte-Höller, Annemieke J.M. Rozemuller, Jurgen A.H.R. Claassen, Benno Küsters and Marcel M. Verbeek

      Article first published online: 16 JUL 2015 | DOI: 10.1111/jnc.13216

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      In this study, we propose that Dickkopf-related protein-3 (Dkk-3) might be a novel Amyloid-β (Aβ) associated protein. We demonstrate that Dkk-3 is expressed in the brain, especially in vessel walls, and co-localizes with Aβ in senile plaques. Furthermore, Dkk-3 levels in cerebrospinal fluid strongly correlate with Aβ40 levels, but were not suitable to discriminate non-demented controls and patients with dementia.

    6. The deubiquitinating enzyme USP46 regulates AMPA receptor ubiquitination and trafficking

      Yuda Huo, Natasha Khatri, Qingming Hou, James Gilbert, Guan Wang and Heng-Ye Man

      Article first published online: 16 JUL 2015 | DOI: 10.1111/jnc.13194

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      Protein ubiquitination is a highly dynamic and reversible process, achieved via the balance between ubiquitination and deubiquitination. The glutamatergic AMPARs, which mediate most of the excitatory synaptic transmission in the brain, are known to be subjected to Nedd4-mediated ubiquitination; however, the deubiquitination process and the responsible deubiquitinating enzymes (DUBs) for mammalian AMPARs remain elusive. We find that AMPARs are subject to K63-type ubiquitination, and identify USP46 as the DUB for AMPARs. USP46 deubiquitinates AMPARs in vitro and in vivo. Up- or down-regulation of USP46 leads to changes in AMPAR ubiquitination, surface expression, and trafficking, as well as the strength of synaptic transmission. USP46-mediated regulation of AMPAR ubiquitination and turnover may play an important role in synaptic plasticity and brain function.

    7. Uncoupling of endothelial nitric oxide synthase in cerebral vasculature of Tg2576 mice

      Anantha Vijay R. Santhanam, Livius V. d'Uscio, Tongrong He, Pritam Das, Steven G. Younkin and Zvonimir S. Katusic

      Article first published online: 15 JUL 2015 | DOI: 10.1111/jnc.13205

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      Existing evidence suggests that Aβ peptides-induced up-regulation of expression and activity of NADPH oxidase causes increased production of superoxide anion (.O2). .O2 can also be converted to hydrogen peroxide (H2O2) by enzymatic activity of superoxide dismutase (SOD) or spontaneous dismutation. Elevation of .O2 and H2O2 might cause oxidation of tetrahydrobiopterin (BH4) to dihydrobiopterin (BH2) and subsequent uncoupling of endothelial nitric oxide synthase (eNOS) (a) thus reducing levels of nitric oxide (NO) and 3′,5′-cyclic guanosine monophosphate (cGMP). Supplementation of BH4 or activation of PPARδ prevents detrimental effects of eNOS uncoupling by restoring bioavailability of BH4 and scavenging of .O2, respectively (b). Activation of PPARδ also increases expression of catalase thereby inactivating H2O2. Generation of H2O2 by uncoupled eNOS in cerebral microvessels of Tg2576 mice is hypothetical.

    8. Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging

      Peter T. Nelson, Wang-Xia Wang, Bernard R. Wilfred, Angela Wei, James Dimayuga, Qingwei Huang, Eseosa Ighodaro, Sergey Artiushin and David W. Fardo

      Article first published online: 15 JUL 2015 | DOI: 10.1111/jnc.13202

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      ABCC9 gene variants are associated with increased risk for hippocampal sclerosis of aging (HS-Aging – a prevalent brain disease with symptoms that mimic Alzheimer's disease). We describe novel ABCC9 variants in human brain, corresponding to altered 3'UTR length, which could lead to targeting by miR-30c. We also determined that the HS-Aging risk mutation is associated with variation in ABCC9 transcript expression.

    9. Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats

      Marjan Popovic, Zeljka Stanojevic, Jelena Tosic, Aleksandra Isakovic, Verica Paunovic, Sasa Petricevic, Tamara Martinovic, Darko Ciric, Tamara Kravic-Stevovic, Vukic Soskic, Sladjana Kostic-Rajacic, Kaveh Shakib, Vladimir Bumbasirevic and Vladimir Trajkovic

      Article first published online: 15 JUL 2015 | DOI: 10.1111/jnc.13198

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      Arylpiperazine dopaminergic/serotonergic ligands reduce neurological symptoms of acute autoimmune encephalomyelitis in rats without affecting the activation of autoreactive immune response, through mechanisms involving a decrease in CNS immune infiltration, as well as direct protection of CNS from immune-mediated damage. These data indicate potential usefulness of arylpiperazine-based compounds in the treatment of neuroinflammatory disorders such as multiple sclerosis.

    10. Reduced dopamine and glutamate neurotransmission in the nucleus accumbens of quinpirole-sensitized rats hints at inhibitory D2 autoreceptor function

      Angélica P. Escobar, Francisca A. Cornejo, Montserrat Olivares-Costa, Marcela González, José A. Fuentealba, Katia Gysling, Rodrigo A. España and María E. Andrés

      Article first published online: 14 JUL 2015 | DOI: 10.1111/jnc.13209

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      Repeated administration of the dopamine D2 receptor agonist quinpirole (QNP) induces locomotor sensitization. We found that the NAc of QNP-sensitized rats has reduced glutamate levels coming from prefrontal cortex together with a decreased phasic and tonic dopamine neurotransmission but a conserved presynaptic D2 receptor function. We suggest that locomotor sensitization is because of increased affinity state of D2 post-synaptic receptors.

    11. Spontaneous seizures in Kcna1-null mice lacking voltage-gated Kv1.1 channels activate Fos expression in select limbic circuits

      Nicole M. Gautier and Edward Glasscock

      Article first published online: 14 JUL 2015 | DOI: 10.1111/jnc.13206

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      Fos protein expression patterns were analyzed using immunohistochemistry to provide the first map of brain regions recruited by spontaneous seizures in mice lacking Kv1.1 channels, an extensively used genetic model of epilepsy. Seizures significantly increased Fos expression in the amygdala and hilus by about fourfold, suggesting an important contribution by extrahippocampal networks to epilepsy in this model.

    12. Tissue transglutaminase-catalysed cross-linking induces Apolipoprotein E multimers inhibiting Apolipoprotein E's protective effects towards amyloid-beta-induced toxicity

      Mieke de Jager, Benjamin Drukarch, Marloes Hofstee, John Brevé, Cornelis A. M. Jongenelen, John G. J. M. Bol and Micha M. M. Wilhelmus

      Article first published online: 7 JUL 2015 | DOI: 10.1111/jnc.13203

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      Cerebral amyloid angiopathy (CAA) is a pathological hallmark of Alzheimer's disease (AD) and characterized by amyloid-β (Aβ) protein deposition and cerebral smooth muscle cell (SMC) death. We found that, in contrast to normal vessels, in CAA apolipoprotein E (ApoE) is cross-linked by tissue transglutaminase (tTG) resulting in stable ApoE complexes. These complexes no longer protect cerebral SMC from Aβ-mediated toxicity. Our findings demonstrate a novel mechanism explaining the Aβ-mediated cerebral SMC cell death characteristic of CAA in AD cases.

    13. 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.

    14. Quantitative targeted absolute proteomics of rat blood–cerebrospinal fluid barrier transporters: comparison with a human specimen

      Yasuo Uchida, Zhengyu Zhang, Masanori Tachikawa and Tetsuya Terasaki

      Article first published online: 8 JUN 2015 | DOI: 10.1111/jnc.13147

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      This is the first study clarifying the absolute protein expression levels of many transporters in the plasma membrane fractions of rat and human choroid plexuses, that is, blood cerebrospinal fluid barrier, by means of quantitative targeted absolute proteomics (QTAP) technique. This study also identified the protein expressions of some transporters including MATE1 and ABCA8 in the choroid plexus for the first time.

    15. Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression

      Massimo Tortarolo, Antonio Vallarola, Dario Lidonnici, Elisa Battaglia, Francesco Gensano, Gabriella Spaltro, Fabio Fiordaliso, Alessandro Corbelli, Stefano Garetto, Elisa Martini, Laura Pasetto, Marinos Kallikourdis, Valentina Bonetto and Caterina Bendotti

      Article first published online: 4 JUN 2015 | DOI: 10.1111/jnc.13154

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      We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co-cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1-G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi-intervention therapies.

  13. 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.

  14. 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.

  15. Short Communications

    1. NCK is critical for the development of deleted in colorectal cancer (DCC) sensitive spinal circuits

      Ciaran Lane, Jiansong Qi and James P. Fawcett

      Article first published online: 19 MAY 2015 | DOI: 10.1111/jnc.13137

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      Reduction in NCK proteins in the developing CNS leads to a reduction in TAG1+ve commissural tract thickness, a reduction in growth cone complexity of DCC+ve spinal interneurons, and a reduction in DCC mRNA. These are consistent with an in vivo role for NCK in the development of critical DCC spinal circuits, and may be important for the normal development of spinal circuits critical for walking.

  16. Original Articles

    1. The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death

      Rumana Akhter, Priyankar Sanphui, Hrishita Das, Pampa Saha and Subhas Chandra Biswas

      Article first published online: 28 APR 2015 | DOI: 10.1111/jnc.13128

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      JNK/c-Jun pathway is shown to be activated in neurons of the Alzheimer's disease (AD) brain and plays a vital role in neuron death in AD models. However, downstream targets of c-Jun in this disease have not been thoroughly elucidated. Our study shows that two important pro-apoptotic proteins, Bim (Bcl-2 interacting mediator of cell death) and Puma (p53 up-regulated modulator of apoptosis) are targets of c-Jun in Aβ-treated neurons. We demonstrate that the JNK/c-jun pathway is activated, in cultures of cortical neurons following treatment with oligomeric Aβ and in AD transgenic mice, and that inhibition of this pathway by selective inhibitor blocks induction of Puma by Aβ. We have also observed functional co-operation of both JNK and p53 pathway in regulation of Puma under Aβ toxicity. Most importantly, we identified a novel AP1-binding site on rat puma gene which is necessary for direct binding of c-Jun with Puma promoter. Thus, our results suggest that both Bim and Puma are target of c-Jun and elucidate the intricate regulation of Puma expression by JNK/c-Jun and p53 pathways in neurons upon Aβ toxicity.

    2. Efficient use of a translation start codon in BDNF exon I

      Indrek Koppel, Jürgen Tuvikene, Ingrid Lekk and Tõnis Timmusk

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13124

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      The brain-derived neurotrophic factor (BDNF) gene contains multiple untranslated 5′ exons alternatively spliced to one common protein-coding 3′ exon. However, exon I contains an in-frame ATG in a favorable translation context. Here, we show that use of this ATG is associated with more efficient protein synthesis than the commonly used ATG in exon IX.

    3. 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.

    4. 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.

  17. 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.

  18. 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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