Poster Abstracts |
P1-C1 Differential role of deltaFosB and delta2deltaFosB in response to stress and drugs of abuse OHNISHI YOSHINORI, OHNISHI YOKO, Nestler Eric J. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY. USA The fosB gene produces two distinct mRNAs by alternative splicing. They encode FosB and deltaFosB, respectively. The latter presents two distinct proteins in the brain, one is deltaFosB, C-terminal truncated form of FosB, and the other is deltaFosB, N-terminal truncated form of deltaFosB. We have reported that deltaFosB accumulates in a region-specific manner in brain after chronic exposure to several types of stress, seizures, or drugs of abuse, and that deltaFosB, acting in the nucleus accumbens (NAc), enhances drug reward and promotes antidepressant-like responses. However, in most cases, these activities were observed under conditions when both deltaFosB and delta2deltaFosB accumulate. This is because endogenous and transgenic expressing mRNA constructs of deltaFosB may permit delta2deltaFosB expression and accumulation due to its extraordinary stability similar to deltaFosB.The goal of the present study was to determine whether the previously reported activities of deltaFosB are dependent on deltaFosB per se or also on delta2deltaFosB. To accomplish this goal, we injected adeno-associated virus expressing several types of fosB isotype and mutant into NAc, and did a broad behavioral battery. The data show that only deltaFosB has obvious antidepressant and pro-addictive effects, suggesting that delta2deltaFosB does not complement deltaFosB action. We are now studying the molecular mechanisms underlying these effects.
P1-C2
Screening and Identifi cation of protein binding partners of deltaFosB using yeast two hybrid system OHNISHI YOKO, OHNISHI YOSHINORI, Nestler Eric J. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY. USA The fosB gene, a member of the AP-1 transcription factor family, has unique properties. it is transcribed into two mature mRNAs encoding FosB and a C-terminal truncated form, deltaFosB. AP-1 complexes consist of Fos family (c-fos, fosB, fra-1, fra-2) and Jun family (c-jun, junB, junD) proteins. Jun proteins are the main component of AP-1 complexes, and activate transcription of target genes as homodimers or as heterodimer with Fos family proteins. On the other hand, Fos family proteins exhibit variable effects on AP-1 transactivity. c-Fos and FosB enhance the transactivity of Jun, while deltaFosB is less active in many cases and, in some cases, can antagonize AP-1 mediated transcription.Our laboratory has focused on deltaFosB function in brain, and have shown that deltaFosB accumulates after prolonged exposure to stress, drugs of abuse, or other stimuli due to its unusual stability. We have shown further than deltaFosB is a key regulatory of drug and stress responses. To elucidate the functions of deltaFosB and other FosB products, we performed yeast two hybrid screening with several fragments of FosB. We identified 8 candidate binding partners with delta2deltaFosB (N-terminal deletion of deltaFosB). Binding of deltaFosB or FosB to several of these candidates has been confirmed in cell culture and in brain, and we have done further behavioral analysis with HSV expression system. Together, this work promises to provide new insight into the mechanisms by which deltaFosB and other FosB gene products regulate brain function and mediate complex behavioral plasticity.
P1-DⅠ5
No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage fi rst-episode schizophrenia Goto Naoki 1, Yoshimura Reiji 1, Kakeda Shingo 2, Moriya Junji 2, Hori Hikaru 1, Hayashi Kenji 1, Sugita Atsuko 1, Nakano Wakako 1, Katsuki Asuka 1, Nishimura Joji 2, Korogi Yukunori 2, Nakamura Jun 1 1 Department of psychiatry, University of Occupational and Environmental Health,Kitakyushu,Japan,
P1-DⅠ6
Evaluation of factors affecting Continuous Performance Test Identical Pairs Version (CPT-IP) score of schizophrenic patients in a Japanese clinical Sample KOIDE TAKAYOSHI 1,Aleksic Branko 1,Kikuchi Tsutomu 1,2, Banno Masahiro 1,Kohmura Kunihiro 1,Adachi Yasunori 1,Kawano Naoko 1, Iidaka Tetsuya 1,Ozaki Norio 1 1 Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
P1-DⅡ2 Association study of Fat-mass and obesity-associated (FTO) gene and body mass index in a Japanese schizophrenia and healthy Japanese population WATANABE SHINYA, Iga Junichi, Nakataki Masahito, Numata Shusuke, Kikuchi Kumiko, Ohmori Tetsuro Department of Psychiatry, University of Tokushima School of Medicine, Tokushima, Japan [Objective] Fat-mass and obesity-associated (FTO) was a gene of unknown function, although genetic variations within the FTO gene have been repeatedly shown to be associated with the risk for obesity in many healthy populations including Japanese population. Meanwhile, patients with schizophrenia have an increased risk for obesity compared to the healthy population. The aim of this study is to elucidate the relationships among FTO gene polymorphisms and BMI in Japanese patients with schizophrenia and healthy subjects. [Method] Clinical parameters including BMI and atypical antipsychotics were evaluated in 351 hospitalized patients with schizophrenia and 342 healthy subjects. Single nucleotide polymorphism (SNP) within FTO gene (rs9939609) known to be associated with obesity was genotyped. Participants provided written informed consent and the institutional ethics committees approved our studies. [Results] A significant difference in genotype frequency between schizophrenia and healthy subjects was detected (P=0.013). There were no significant differences in age,sex and BMI between schizophrenia and healthy subjects. A significant effect of the rs9939609 polymorphism on BMI was found in healthy subjects but not in patients. [Conclusion] In our investigation, it is suggested that rs9939609 in FTO gene may play roles in the pathophysiology of Japanese schizophrenia and in the regulation of BMI in healthy subjects. No significant associations between BMI and rs9939609 in patients raise a possibility that other factors including food intake and energy consumption may influence BMI.
P1-DⅡ6 The KCNH2 gene is associated with neurocognition and the risk of Schizophrenia OHI KAZUTAKA1,2,3, Hashimoto Ryota 1,3,4, Yasuda Yuka 1,3, Fukumoto Motoyuki 1,3, Yamamori Hidenaga 1,3,5, Kamino Kouzin 1,2, Morihara Takashi 1, Iwase Masao1, Kazui Hiroaki 1, Takeda Masatoshi 1,4
P1-DⅢ1 RELA Gene is associated with risk for schizophrenia and defi cits in prepulse Inhibition Hashimoto Ryota 1,2,3,10, Ohi Kazutaka 2,3, Yasuda Yuka 2,3, Fukumoto Motoyuki 2,3, Yamamori Hidenaga 2,3,4, Takahashi Hidetoshi 2,3, Iwase Masao 2, Okochi Tomo 3,5, Kazui Hiroaki 2, Saitoh Osamu 6, Tatsumi Masahiko 7, Iwata Nakao 3,5, Ozaki Norio 8, Kamijima Kunitoshi 9, Kunugi Hiroshi 10, Takeda Masatoshi 1,2
P1-DⅢ5 Amino acid neurotransmission in schizophrenia patients and the effects of antipsychotic medication: A proton magnetic resonance spectroscopy study NAKATAKI MASAHITO 1, KUBO HIROKO 2, IGA JUN-ICHI 2, WATANABE SHINYA 2, SUMITANI SATSUKI 2, HARADA MASAFUMI 3, OHMORI TETSURO 2
P1-DⅥ2 Adjunctive treatment with low-dosage pramipexole for risperidoneinduced hyperprolactinemia and sexual dysfunction in a male patient with schizophrenia ISHITOBI MAKOTO, KOSAKA HIROTAKA, SHUKUNAMI KEN-ICHI, MURATA TETSUHITO, WADA YUJI Department of Neuropsychiatry, University of Fukui, Fukui, Japan Hyperprolactinemia is a frequent and severe side effect of antipsychotic treatment. Adjunctive dopamine D2 receptor (partial) agonist is one of the strategies for treatment of hyperprolactinemia. However, the utility of an adjunctive dopamine D2 (partial) agonist in managing antipsychoticinduced hyperprolactinemia without worsening psychosis in patients with schizophrenia remains controversial. Pramipexole, a preferential dopamine D3 receptor agonist, is currently used for treatment of idiopathic Parkinsons disease. We report the case of a 34-year-old male patient with schizophrenia who showed hyperprolactinemia induced by risperidone (2 mg/day) and ED, each of which was improved successfully without worsening psychosis by adjunctive treatment with low-dosage pramipexole (0.25 mg/day). Pramipexole, a preferential dopamine D3 receptor agonist with an approximately eight-fold preference for D3 receptors and less affinity for D1, D2, and D4, might be advantageous for reducing risks of exacerbating psychosis because of its lower affinity for D2 receptors. In some cases, adjunctive low-dosage pramipexole might be sufficient for early improvement of ED associated with antipsychoticinduced hyperprolactinemia.
P1-KⅠ1 Association analysis between the 1,alpha-Hydroxylase (CYP27B1) gene polymorphisms and late-onset Alzheimer's disease UTSUNOMIYA KENSUKE 1, SHINKAI TAKAHIRO 1, YAMADA KENJI 1, SAKATA SHINICHI 4,CHEN HSIN-I 2, OHMORI OSAMU 3, NAKAMURA JUN1
INTRODUCTION: Vitamin D may help to prevent neurodegeneration because it plays a key role in the expression of neurotrophic factors, the prevention of oxidative stress, calcium homeostasis, detoxification. Recent studies have reported that low levels of serum 25-hydroxyvitaminD (25[OH]D) were associated with an increased risk of substantial cognitive decline and dementia. 1,25-(OH)2D, the natural vitamin D receptor (VDR) ligand is derived from its precursor 25(OH)D by the enzyme 1,alpha(OH)ase encoded by the CYP27B1 gene. METHODS: We examined an association of polymorphisms at vitamin D metabolism enzyme, CYP27B1 in a Japanese sample of late-onset Alzheimer's disease (LOAD) (over 100 LOAD cases and 200 normal controls). RESULTS: Although our preliminary data does not suggest a robust association, analysis with complete data set is currently undergoing to clarify the relationship between CYP27B1 polymorphisms and LOAD. DISCUSSION: Several lines of findings suggest a possible role of in CYP27B1 and Alzheimer's disease (AD) pathogenesis. Further studies on CYP27B1 and other vitamin D pathway genes in AD will be needed.
P2-AⅡ1 The effect of corticosterone to immunoreactive cell lines NAKATANI YOSHIHIKO, AMANO TAKU, TSUJI MINORU, TAKEDA HIROSHI Division of Pharmacology, School of Pharmacy, International University of Health and Welfare, Ohtawara, Japan Corticosterone, which is classified as steroid hormone, is known as one of the glucocorticoids which have broad effects, such as regulation of glucose metabolism, the reaction of immune system and stress response, in many species. In general, it has been known that corticosterone involves to the stress response and is defined as stress hormone. After the hormonereceptor complex is formed in the cytoplasma, that complex translocates from cytoplasma to nucleus and regulates DNA transcription. Tremendous literatures have reported that neuron is vulnerable under the stress condition. However, the effect of corticosterone to the immunoreactive cell still has remained unclear though it is clear that the immune response cells play an important role under the stress condition. In this study, we focused to the microglia and macrophage, which are important for immunoreactions, and investigated the effect of corticosterone to the cell viability using several cell lines. Under the corticosterone existing culture condition, the proliferation of immunoreactive cells (BV-2 and RAW264.7) was suppressed drastically. On the other hand, neural type cell (Neuro2a, SH-SY5Y and RN46A) didn't show any change in cell proliferation. This inhibitory effect to the cell proliferation recovered by the glucocorticoid receptor antagonist, mifepristone, treatment, but not the mineralcorticoid receptor antagonist, spironolactone, treatment. In conclusion, corticosterone may play a key role to immune and stress response of microglia and macrophage via glucocorticoid receptor in the brain.
P2-AⅡ4 Npas4 regulates neurite outgrowth and phosphoryation of synapsin I Yun Jaesuk1,Taku Nagai1,Yoko Hibi1,Keisuke Kuroda2, Kozo Kaibuchi2,Kiyofumi Yamada 1
We have previously reported that the mRNA levels of neuronal PAS domain protein 4 (Npas4), a brain specific basic helix-loophelix transcription factor, are decreased in the hippocampus of mice following a chronic social isolation or restriction stress. A recent study has demonstrated that Npas4 regulates the development of GABAergic inhibitory neurons. In the presents study, treatment with LiCl in Neuro2a cells resulted in an increase in Npas4 mRNA and phosphorylatedsynapsin I protein expression levels, which were associated with the neurite outgrowth. The knock down of Npas4 significantly inhibited the neurite outgrowth of Neuro2a cells induced by LiCl whereas the overexpression of Npas4 gene potentiated it. Overexpression of Npas4 in Neuro2a cells led to increase in the expression level of NeuN and phosphorylated synapsin I respectively. In primary cultured hippocampal neurons, Npas4 overexpression significantly increased in the protein level of phosphorylated synapsin I. These results suggest that Npas4 plays a role in the structural and functional plasticity of neurons.
P2-BⅡ1 Reduced calcium/calmodulin-dependent protein kinase II activity in the hippocampus is associated with impaired cognitive function in 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice MORIGUCHI SHIGEKI, YABUKI YASUSHI, FUKUNAGA KOHJI Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan Parkinson's disease (PD) patients show deficit of cognitive functions during the early stage in PD. The dopaminergic neurotoxin, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced neurodegeneration causes an injury of the basal ganglia and revels PD-like behaviors. Here we demonstrated that deficit in cognitive functions in MPTP-treated mice is associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) autophoshorylation and impaired LTP in the hippocampal CA1 region. Mice were injected once a day for 5 days with MPTP (25 mg/kg i.p.). The impaired motor coordination was observed 1to 2 weeks after MPTP treatment as assessed by a rota-rod and a beam-walking tasks. In immunoblot analyses, the protein levels of tyrosine hydroxylase and CaMKII autophoshorylation in the striatum were significantly decreased 1week after MPTP treatment. By contrast, deficits of cognitive function were observed 3 to 4 weeks after MPTP treatment. Impairment of long-term potentiation (LTP) in the hippocampal CA1 region was also impaired in MPTP-treated mice. Concomitant with impaired LTP, CaMKII autophosphorylation was significantly decreased 3 weeks after MPTP treatment in the hippocampal CA1 region. Finally, the reduced CaMKII autophosphorylation was closely associated with reduced GluR1 (Ser-831) phosphorylation in the hippocampal CA1 region of MPTP-treated mice. Taken together, decreased CaMKII activity with concomitant impaired LTP in the hippocampus likely account for the learning disability observed in MPTP-treated mice.
P2-BⅡ2 Difference in the effect of Imipramine and GBR12909 on the Runway method using priming stimulation effect (PSE) of the intracranial selfstimulation (ICSS) behavior EZUMI SATORU 1, KAWASAKI YOICHI 1, SAGARA HIDENORI 2, KITAMURA YOSHIHISA 3, MATSUNAGA HISASHI 1, GOMITA YUTAKA 4, SENDO TOSHIAKI 1
P2-GⅥ1 Predicting antipsychotic plasma concentrations before titrating the dose: a population pharmacokinetic study UCHIDA HIROYUKI1, David Mamo 2,4, Pollock Bruce 2,4, Suzuki Takefumi 1,5, Takeuchi Hiroyoshi 1, Nomura Kensuke 6, Tsunoda Kenichi 3, Watanabe Koichiro 1, Bies Robert 7
Background: Due to a high interindividual variability in peripheral pharmacokinetic parameters, robustly predicting antipsychotic plasma concentrations before changing a dose for each individual has been a challenge, which can be overcome with population pharmacokinetic techniques in theory.
P2-GⅥ4 The evolution of antipsychotic switch and polypharmacy in natural practice - a longitudinal perspective TSUTSUMI CHISA 1, TSUTSUMI YUICHIRO 2, IMASAKA YASUSHI 3,4, KIMURA YOSHIE 3,6,WATANABE KOICHIRO 3,5, TOMITA MASAYUKI 5,6, HIRANO JINICHI 3,4,6, MIZUNO YUYA 7, DEN RYOSUKE 1, ISHIDUKI TOMOMI 8, NAKAGAWA ATSUO 5,9, KITAHATA RYOSUKE 10, UCHIDA HIROYUKI 5,6
Objective: Most patients with schizophrenia first start with a single antipsychotic, and yet most finally end up 'switching' or using 'polypharmacy'. The objective of this study was to examine the evolution of antipsychotic switch and polypharmacy in the real-world from a longitudinal perspective.
P2-HⅢ3 Effect of chronic fl uoxetine treatment on dopamine D1 receptor signaling in the hippocampal dentate gyrus KUROIWA MAHOMI1, SOTOGAKU NAOKI 1, SHUTO TAKAHIDE 1, MIYAKAWA TSUYOSHI 2, NISHI AKINORI 1
Major depression is a psychiatric disorder with high lifetime prevalence. Antidepressants have been widely used to treat major depression, although the mechanisms underlying their therapeutic effects are not fully understood. Recently, a selective serotonin reuptake inhibitor, fluoxetine, is reported to induce the dematuration of mature granule cells in the hippocampal dentate gyrus, in addition to the facilitation of adult neurogenesis. It is also reported that granule cells with features of immature cells show the decreased expression of calbindin, a marker of mature granule cells, and the increased expression of dopamine D1 receptors. In this study, we investigated dopamine D1 receptor signaling by monitoring the phosphorylation of PKA substrates including DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) in dentate gyrus slices of C57BL/6 mice, which were treated with fluoxetine (15 mg/kg/day) for 14 days. Treatment of slices with a D1 receptor agonist, SKF81297, increased the phosphorylation of DARPP-32 at Thr34 in a dose dependent manner. The effect of SKF81297 (10 μM) was enhanced in fluoxetine-treated mice. The results suggest that the enhancement of D1 receptor signaling in dentate gyrus by chronic fluoxetine treatment may contribute to the therapeutic action of antidepressants.
P2-IⅢ3 SOCS3, a candidate gene for the molecular effects of lithium and pathophysiology of MDD IGA JUNICHI, KIKUCHI KUMIKO, TAYOSHI SUMIKO, NAKATAKI MASAHITO, WATANABE SHINYA, NUMATA SHUSUKE, OHMORI TETSURO Department of Psychiatry, Course of Integrated Brain Sciences, University of Tokushima School of Medicine, Tokushima, Japan Objectives: To elucidate the association between SOCS3 and molecular effects of lithium and pathophysiology of MDD, we studied the SOCS3 gene expression changes in leukocytes of healthy individuals during lithium administration and MDD patients during antidepressant treatment.Methods: 8 healthy male subjects participated in the first study. Lithium was prescribed for 2 weeks enough to reach therapeutic serum concentration (0.6-1.0mM). Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), 1-week, 2-week medication and post-2-week (2-week after stopping medication). Gene expression profiling was performed at each time point using Agilent G4112F Whole Human Genome arrays and real-time PCR. In the second study, we compared SOCS3 gene expression in the leukocytes between 27 MDD patients and healthy controls. Results: In the first study, leukocyte counts were significantly increased at 2-week compared with baseline and normalized at post-2-week. Pathway analysis based on the genes which were changed more than 2 folds revealed that Interleukin 6 (IL6) pathway including SOCS3 gene was regulated by lithium. We also confirmed that SOCS3 was significantly decreased by lithium using real-time PCR. In the second study, SOCS3 was significantly lower in MDD patients compared to healthy controls and was significantly increased to the control level by antidepressant treatment.Conclusions: Our investigation suggests that SOCS3 may be implicated in the molecular action of lithium and pathophysiology of MDD.
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