研究者詳細 - 田中　謙二

論文 - 田中　謙二

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Increased numbers of oligodendrocyte lineage cells in the optic nerves of cerebroside sulfotransferase knockout mice

Kajigaya Hitoshi, Tanaka Kenji F., Hayashi Akiko, Suzuki Ayaka, Ishibashi Tomoko, Ikenaka Kazuhiro, Baba Hiroko

Proceedings of the Japan Academy Series B: Physical and Biological Sciences 87 （ 7 ） 415 - 424 2011年

ISSN 0386-2208

Sulfatide is a myelin glycolipid that functions in the formation of paranodal axoglial junctions in vivo and in the regulation of oligodendrocyte differentiation in vitro. Cerebroside sulfotransferase (CST) catalyzes the production of two sulfated glycolipids, sulfatide and proligodendroblast antigen, in oligodendrocyte lineage cells. Recent studies have demonstrated significant increases in oligodendrocytes from the myelination stage through adulthood in brain and spinal cord under CST-deficient conditions. However, whether these result from excess migration or in situ proliferation during development is undetermined. In the present study, CST-deficient optic nerves were used to examine migration and proliferation of oligodendrocyte precursor cells (OPCs) under sulfated glycolipid-deficient conditions. In adults, more NG2-positive OPCs and fully differentiated cells were observed. In developing optic nerves, the number of cells at the leading edge of migration was similar in CST-deficient and wild-type mice. However, BrdUD proliferating OPCs were more abundant in CST-deficient mice. These results suggest that sulfated glycolipids may be involved in proliferation of OPCs in vivo. ©2011 The Japan Academy.

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Flexible Accelerated STOP Tetracycline Operator-Knockin (FAST)

Tanaka Kenji F., Ahmari Susanne E., Leonardo E. David, Richardson-Jones Jesse W., Budreck Elaine C., Scheiffele Peter, Sugio Shouta, Inamura Naoko, Ikenaka Kazuhiro, Hen René

Biological Psychiatry 67 （ 8 ） 770 - 773 2010年04月

ISSN 0006-3223

We created the Flexible Accelerated STOP Tetracycline Operator (tetO)-knockin (FAST) system, an efficient method for manipulating gene expression in vivo to rapidly screen animal models of disease. A single gene targeting event yields two distinct knockin mice-STOP-tetO and tetO knockin-that permit generation of multiple strains with variable expression patterns: 1) knockout, 2) Cre-mediated rescue, 3) tetracycline-controlled transcriptional activator (tTA)-mediated misexpression, 4) tetracycline-controlled transcriptional activator (tTA)-mediated overexpression, and 5) tetracycline-controlled transcriptional silencer (tTS)-mediated conditional knockout/knockdown. Using the FAST system, multiple gain-of-function and loss-of-function strains can therefore be generated on a time scale not previously achievable. These strains can then be screened for clinically relevant abnormalities. We demonstrate the flexibility and broad applicability of the FAST system by targeting several genes encoding proteins implicated in neuropsychiatric disorders: Mlc1, neuroligin 3, the serotonin 1A receptor, and the serotonin 1B receptor. © 2010 Society of Biological Psychiatry.

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Organotypic tissue culture of adult rodent retina followed by particle-mediated acute gene transfer in vitro

Moritoh Satoru, Tanaka Kenji F., Jouhou Hiroshi, Ikenaka Kazuhiro, Koizumi Amane

PLoS One 5 （ 9 ） 2010年

ISSN 1932-6203

Background: Organotypic tissue culture of adult rodent retina with an acute gene transfer that enables the efficient introduction of variable transgenes would greatly facilitate studies into retinas of adult rodents as animal models. However, it has been a difficult challenge to culture adult rodent retina. The purpose of this present study was to develop organotypic tissue culture of adult rodent retina followed by particle-mediated acute gene transfer in vitro. Methodology/Principal Findings: We established an interphase organotypic tissue culture for adult rat retinas (>P35 of age) which was optimized from that used for adult rabbit retinas. We implemented three optimizations: a greater volume of Ames' medium (>26 mL) per retina, a higher speed (constant 55 rpm) of agitation by rotary shaker, and a greater concentration (10%) of horse serum in the medium. We also successfully applied this method to adult mouse retina (>P35 of age). The organotypic tissue culture allowed us to keep adult rodent retina morphologically and structurally intact for at least 4 days. However, mouse retinas showed less viability after 4-day culture. Electrophysiologically, ganglion cells in cultured rat retina were able to generate action potentials, but exhibited less reliable light responses. After transfection of EGFP plasmids by particle-mediated acute gene transfer, we observed EGFP-expressing retinal ganglion cells as early as 1 day of culture. We also introduced polarized-targeting fusion proteins such as PSD95-GFP and melanopsin-EYFP (hOPN4-EYFP) into rat retinal ganglion cells. These fusion proteins were successfully transferred into appropriate locations on individual retinal neurons. Conclusions/Significance: This organotypic culture method is largely applicable to rat retinas, but it can be also applied to mouse retinas with a caveat regarding cell viability. This method is quite flexible for use in acute gene transfection in adult rodent retina, replacing molecular biological bioassays that used to be conducted in isolated cultured cells. © 2010 Moritoh et al.

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A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure

Yadav Vijay K., Oury Franck, Suda Nina, Liu Zhong Wu, Gao Xiao Bing, Confavreux Cyrille, Klemenhagen Kristen C., Tanaka Kenji F., Gingrich Jay A., Guo X. Edward, Tecott Laurence H., Mann J. John, Hen Rene, Horvath Tamas L., Karsenty Gerard

Cell 138 （ 5 ） 976 - 989 2009年09月

ISSN 0092-8674

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online. © 2009 Elsevier Inc. All rights reserved.

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Synergistic neurochemical and behavioural effects of acute intrahippocampal injection of brain-derived neurotrophic factor and antidepressants in adult mice

Deltheil Thierry, Tanaka Kenji, Reperant Christelle, Hen René, David Denis J., Gardier Alain M.

International Journal of Neuropsychopharmacology 12 （ 7 ） 905 - 915 2009年08月

ISSN 1461-1457

Preclinical data support the view that brain-derived neurotrophic factor (BDNF) and serotonergic systems regulate circuits involved in affective disorders. The present study examined neurochemical and behavioural consequences of an acute intrahippocampal injection of BDNF combined with an antidepressant by using in-vivo intracerebral microdialysis in the ventral hippocampus (vHi) in conscious mice and behavioural paradigms predictive of antidepressant and anxiolytic-like effects [the mouse forced swim test (FST), the open-field (OF) paradigm and the elevated plus maze (EPM)]. Neurochemical data revealed that BDNF (100 ng) potentiated the effects of the systemic administration of a serotonin selective reuptake inhibitor (SSRI; paroxetine 4 mg/kg i.p.) and that of a locally applied citalopram perfusion on dialysate 5-HT levels in the vHi. These neurochemical changes correlated with behavioural data since, in the FST, antidepressant-like activity of paroxetine as measured on swimming behaviour was potentiated by BDNF. These data suggest an interesting synergy between BDNF and SSRI on antidepressant-like activity. Furthermore, in both the OF and EPM paradigms BDNF induced an anxiogenic-like activity, whereas paroxetine prevented this effect. Finally, the neurochemical and behavioural effects of BDNF on the serotonergic system might occur at both pre- and post-synaptic levels since by using in-situ hybridization, we showed that TrkB-R mRNA was expressed in the hippocampus and the dorsal raphe nucleus in adult mice. Taken together the neurochemical and behavioural effects of BDNF suggest that these behavioural changes were mediated by increases in 5-HT neurotransmission in vHi. Thus a BDNF+SSRI combination may offer new alternatives to treat mood disorders. Copyright © 2009 CINP.

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Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities

Tanaka Hisataka, Ma Jianmei, Tanaka Kenji F., Takao Keizo, Komada Munekazu, Tanda Koichi, Suzuki Ayaka, Ishibashi Tomoko, Baba Hiroko, Isa Tadashi, Shigemoto Ryuichi, Ono Katsuhiko, Miyakawa Tsuyoshi, Ikenaka Kazuhiro

Journal of Neuroscience 29 （ 26 ） 8363 - 8371 2009年07月

ISSN 0270-6474

Conduction velocity (CV) of myelinated axons has been shown to be regulated by oligodendrocytes even after myelination has been completed. However, how myelinating oligodendrocytes regulate CV, and what the significance of this regulation is for normal brain function remain unknown. To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1^tg/- mice) at 2 months of age. At this stage, the plp1^tg/- mice have an unaffected myelin structure with a normally appearing ion channel distribution, but the CV in all axonal tracts tested in the CNS is greatly reduced. We also found decreased axonal diameters and slightly abnormal paranodal structures, both of which can be a cause for the reduced CV. Interestingly the plp1^tg/- mice showed altered anxiety-like behaviors, reduced prepulse inhibitions, spatial learning deficits and working memory deficit, all of which are schizophrenia-related behaviors. Our results implicate that abnormalities in the neuron-glia interactions at the paranodal junctions can result in reduced CV in the CNS, which then induces behavioral abnormalities related to schizophrenia. Copyright © 2009 Society for Neuroscience.

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LDL-receptor related protein five controls bone formation by inhibiting serotonin synthesis in the duodenum

Yadav Vijay K., Ryu Je Hwang, Suda Nina, Tanaka Kenji F., Gingrich Jay A., Schütz Günther, Glorieux Francis H., Chiang Cherie Y., Zajac Jeffrey D., Insogna Karl L., John Mann J., Hen Rene, Ducy Patricia, Karsenty Gerard

Obstetrical and Gynecological Survey 64 （ 4 ） 240 - 242 2009年04月

ISSN 0029-7828

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Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum

Yadav Vijay K., Ryu Je Hwang, Suda Nina, Tanaka Kenji F., Gingrich Jay A., Schütz Günther, Glorieux Francis H., Chiang Cherie Y., Zajac Jeffrey D., Insogna Karl L., Mann J. John, Hen Rene, Ducy Patricia, Karsenty Gerard

Cell 135 （ 5 ） 825 - 837 2008年11月

ISSN 0092-8674

Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of β-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a β-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass. © 2008 Elsevier Inc. All rights reserved.

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Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice

Deltheil T., Guiard B. P., Cerdan J., David D. J., Tanaka K. F., Repérant C., Guilloux J. P., Coudoré F., Hen R., Gardier A. M.

Neuropharmacology 55 （ 6 ） 1006 - 1014 2008年11月

ISSN 0028-3908

Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRI) act as indirect agonists of serotonin (5-HT) receptors. Although these drugs produce a rapid blockade of serotonin transporters (SERTs) in vitro, several weeks of treatment are necessary to observe clinical benefits. This paradox has not been solved yet. Recent studies have identified modifications of intracellular signaling proteins and target genes that could contribute to antidepressant-like activity of SSRI (e.g., increases in neurogenesis and BDNF protein levels), and may explain, at least in part, their long delay of action. Although these data suggest a positive regulation of 5-HT on the expression of the gene coding for BDNF, the reciprocal effects of BDNF on brain 5-HT neurotransmission remains poorly documented. To study the impact of BDNF on serotonergic activity, a dual experimental strategy was used to analyze neurochemical and behavioral consequences of its decrease (strategy 1) or increase (strategy 2) in the brain of adult male mice. (1) In heterozygous BDNF+/- mice in which brain BDNF protein levels were decreased by half, an enhancement of basal extracellular 5-HT levels (5-HText) that induced a down-regulation of SERT, i.e., a decrease in its capacity to reuptake 5-HT, was found in the hippocampus. In addition, the SSRI, paroxetine, failed to increase hippocampal 5-HText in BDNF+/- mice, while it produces robust effects in wild-type littermates. Thus, BDNF+/- mice can be viewed as an animal model of genetic resistance to serotonergic antidepressant drugs. (2) In wild-type BDNF+/+ mice, the effects of intra-hippocampal (vHi) injection of BDNF (100 ng) in combination with a SSRI was examined by using intracerebral microdialysis and behavioral paradigms that predict an antidepressant- and anxiolytic-like activity of a molecule [the forced swim test (FST) and the open field paradigm (OF) respectively]. BDNF induced a rapid and transient increase in paroxetine response on 5-HText in the adult hippocampus, which was correlated with a potentiation of its antidepressant-like activity in the FST. The effects of BDNF were selectively blocked by K252a, an antagonist of its high-affinity TrkB receptor. Such a correlation between neurochemical and behavioral effects of [BDNF + SSRI] co-administration suggests that its antidepressant-like activity is linked to the activation of 5-HT neurotransmission in the adult hippocampus. BDNF also had a facilitatory effect on anxiety-like behavior in the OF test, and paroxetine prevented this anxiogenesis. What was the mechanism by which BDNF exerted these latter effects? Surprisingly, by using zero net flux method of quantitative microdialysis in vivo, we found that an intra-hippocampal BDNF injection in wild-type mice decreased the functional activity of SERT as observed in BDNF+/- mice. However, the decreased capacity of SERT to reuptake 5-HT was not associated to an increase in basal 5-HText in the hippocampus of WT mice. Interestingly, using in situ hybridization experiments indicated that TrkB receptor mRNA was expressed in the hippocampus and dorsal raphe nucleus in adult mice suggesting that the neurochemical and behavioral effects of intra-hippocampal BDNF injection can mobilize both pre- and post-synaptic elements of the brain 5-HT neurotransmission. Taken together, these set of experiments unveiled a relative opposition of neurochemical and behavioral responses following either a decrease (in BDNF+/- mutant mice) or an increase in brain BDNF levels (bilateral intra-hippocampal injection) in adult mice. In view of developing new antidepressant drug strategy, a poly-therapy combining BDNF with a chronic SSRI treatment could thus improve the efficacy of current medications. © 2008 Elsevier Ltd. All rights reserved.

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GFAP aggregates in the cochlear nerve increase the noise vulnerability of sensory cells in the organ of Corti in the murine model of Alexander disease

Masuda Masatsugu, Tanaka Kenji F., Kanzaki Sho, Wakabayashi Kenichiro, Oishi Naoki, Suzuki Takafumi, Ikenaka Kazuhiro, Ogawa Kaoru

Neuroscience Research 62 （ 1 ） 15 - 24 2008年09月

ISSN 0168-0102

Outer hair cell (OHC) loss in the auditory sensory epithelium is a primary cause of noise-induced sensory-neural hearing loss (SNHL). To clarify the participation of glial cells in SNHL, we used an Alexander disease (AxD) mouse model. These transgenic mice harbor the AxD causal mutant of the human glial fibrillary acidic protein (GFAP) under the control of the mouse GFAP promoter. It is thought that GFAP aggregates compromise the function of astrocytes. In the auditory pathway, the formation of GFAP aggregates was observed only in GFAP-positive cells of the cochlear nerve. The presence of GFAP aggregates did not change auditory function at the threshold level. To assess the change in vulnerability to auditory excitotoxicity, both transgenic and control mice were treated with intense noise exposure. Auditory threshold shifts were assessed by auditory brainstem responses (ABR) at 1 and 4 weeks after noise exposure, and OHC damage was analyzed by quantitative histology at 4 weeks after exposure. Transgenic mice showed more severe ABR deficits and OHC damage, suggesting that cochlear nerve glial cells with GFAP aggregates play a role in noise susceptibility. Thus, we should focus more on the roles of cochlear nerve glial cells in SNHL. © 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Termination of lesion-induced plasticity in the mouse barrel cortex in the absence of oligodendrocytes

Toda Tomohisa, Hayakawa Itaru, Matsubayashi Yutaka, Tanaka Kenji, Ikenaka Kazuhiro, Lu Qing Richard, Kawasaki Hiroshi

Molecular and Cellular Neuroscience 39 （ 1 ） 40 - 49 2008年09月

ISSN 1044-7431

Termination of developmental plasticity occurs at specific points in development, and the mechanisms responsible for it are not well understood. One hypothesis that has been proposed is that oligodendrocytes (OLs) play an important role. Consistent with this, we found that OLs appeared in the mouse somatosensory cortex at the end of the critical period for whisker lesion-induced barrel structural plasticity. To test this hypothesis, we used two mouse lines with defective OL differentiation: Olig1-deficient and jimpy. In Olig1-deficient mice, although OLs were totally absent, the termination of lesion-induced plasticity was not delayed. The timing was normal even when the cytoarchitectonic barrel formation was temporarily blocked by pharmacological treatment in Olig1-deficient mice. Furthermore, the termination was not delayed in jimpy mice. These results demonstrate that, even though OLs appear at the end of the critical period, OLs are not intrinsically necessary for the termination of lesion-induced plasticity. Our findings underscore a mechanistic distinction between the termination of thalamocortical axonal plasticity in the barrel cortex and that in the visual cortex, in which OL-derived Nogo-A/B was recently suggested to be essential. © 2008 Elsevier Inc. All rights reserved.

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Genetic fate mapping of Olig2 progenitors in the injured adult cerebral cortex reveals preferential differentiation into astrocytes

Tatsumi Kouko, Takebayashi Hirohide, Manabe Takayuki, Tanaka Kenji F., Makinodan Manabu, Yamauchi Takahira, Makinodan Eri, Matsuyoshi Hiroko, Okuda Hiroaki, Ikenaka Kazuhiro, Wanaka Akio

Journal of Neuroscience Research 86 （ 16 ） 3494 - 3502 2008年

ISSN 0360-4012

Olig2 is a basic helix-loop-helix (bHLH) transcription factor essential for development of motoneurons and oligodendrocytes. It is known that Olig2⁺ cells persist in the central nervous system (CNS) from embryonic to adult stages and that the number of Olig2⁺ progenitors increases in the injured adult CNS. Recent studies have demonstrated an inhibitory action of Olig2 on neurogenesis in adult CNS, but the fate of Olig2⁺ cells in the injured state remains largely unknown. To trace directly the fate of Olig2 cells in the adult cerebral cortex after injury, we employed the CreER/loxP system to target the olig2 locus. In this genetic tracing study, green fluorescent protein (GFP) reporter-positive cells labeled after cryoinjury coexpressed glial fibrillary acidic protein (GFAP), an astrocytic marker. Electron microscopy also showed that GFP⁺ cells have the ultrastructural characteristics of astrocytes. Furthermore, GFP⁺ cells labeled before injury, most of which had been NG2 cells, also produced bushy astrocytes. Here we show direct evidence that Olig2⁺ cells preferentially differentiate into astrocytes, which strongly express GFAP, in response to injury in the adult cerebral cortex. These results suggest that reactive astrocytes, known to be the main contributors to glial scars, originate, at least in part, from Olig2⁺ cells. © 2008 Wiley-Liss, Inc.

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Generation of mice with glial cell dysfunction

Tanaka Kenji, Hae Ung Lee, Ikenaka Kazuhiro

Brain and Nerve 59 （ 7 ） 747 - 753 2007年07月

ISSN 0006-8969

To examine astrocytic function, we have developed model mice harboring astrocyte-specific disease causal gene and tried to examine astrocytic function in vivo. Alexander disease, megalencephalic leukodystrophy with subcortical cysts (MLC), and autistic spectrum disorder with neuroligin 3/4 mutations are known to be astrocyte-specific disease so far. First of all, we have established Alexander disease model mouse. Alexander disease is caused by coding mutation in glial fibrillary acidic protein (GFAP) and mutant GFAP forms inclusion bodies, called Rosenthal fibers, in astrocytes. Its pathophysiology is still unknown. We generated transgenic mice that express human GFAP R239H mutant under the control of mouse GFAP promoter. Lines with single copy exhibited weak human GFAP expression in astrocytes that did not produce aggregates despite the existence of mutation, whereas lines with multi copies exhibited strong expression and the formation of aggregates, starting at P14. The line with aggregates showed higher sensitivity to kainate than the line without them, whose sensitivity was not different from the wild type mouse, suggesting that the presence of GFAP aggregates but not the presence of mutant GFAP altered the sensitivity. Changes in several electrophysiological parameters, including facilitation of LTP, were also observed in this model mouse. We believe that this transgenic line is a useful tool to study astrocytic function in vivo.

Murine model of Alexander disease

Tanaka Kenji F., Takebayashi Hirohide, Yamazaki Yoshihiko, Ono Katsuhiko, Naruse Masae, Iwasato Takuji, Itohara Shigeyoshi, Kato Hiroshi, Ikenaka Kazuhiro

GLIA 55 （ 6 ） 617 - 631 2007年04月

ISSN 0894-1491

Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark is the formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist of GFAP and several heat shock proteins. The presence of mutant GFAP would appear to be involved in RF formation; however, overproduction of wild type human GFAP in mouse brain also results in RF formation. Here, we investigated the in vivo conditions leading to formation of RF-like aggregates. We used transgenic mice (mouse GFAP promoter-human GFAP cDNA with R239H mutation) in which the dosage of the GFAP transgene could be manipulated within the same genetic locus. We found that the presence of mutant GFAP per se was insufficient for aggregate formation. Instead, a 30% increase in GFAP content over that in wild type was also required. GFAP aggregates upregulated endogenous GFAP and nestin gene expression, and intermediate filament structure revealed by immunostaining was fragmented under these conditions. However, overall morphology of astrocytes, including their fine processes, was unaffected. In this transgenic animal model, mice did not show megalencephaly, leukodystrophy, or seizure characteristic of Alexander disease with R239H mutation. Nevertheless, their mortality after kainate challenge was dramatically increased, whereas transgenic mice lacking aggregates exhibited mortality similar to that of wild type mice. These results indicate that the presence of GFAP aggregates containing mutant GFAP is not sufficient to induce a major phenotype of Alexander disease, even though it causes some abnormalities in the mouse. © 2007 Wiley-Liss, Inc.

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Induced expression of cathepsins and cystatin C in a murine model of demyelination

Ma Jianmei, Tanaka Kenji F., Yamada Gen, Ikenaka Kazuhiro

Neurochemical Research 32 （ 2 ） 311 - 320 2007年02月

ISSN 0364-3190

While proteolytic enzymes are involved in the pathogenesis of multiple sclerosis (MS), the involvement of cathepsins has not been characterized in detail. To better understand the role of cathepsins, cDNA microarray analysis was used to study the brains of proteolipid protein transgenic (plp^tg /-) mice, an animal model that closely mimics the failure of remyelination in MS. Analysis revealed upregulated expression of cathepsins L, H and B and their inhibitor, cystatin C. By in situ hybridization, the induction of cathepsins was primarily limited to microglia/macrophages of the white matter, with continuous expression from 2 to 8 months of age. Elevated protein level of cathepsins was confirmed at 4 months of age. In contrast, elevated expression of cystatin C was found in astrocytes. The ratio of microglia/macrophages to astrocytes increased throughout the course of demyelination, suggesting that the ratio of secreted cathepsins to cystatin C increased during that period. We propose that in MS, remyelination may be impaired by increasing activity of cathepsins inadequately controlled by cystatin C. © 2006 Springer Science+Business Media, LLC.

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Fluoro-Jade

Tanaka Kenji F., Ochi Nobuhiko, Hayashi Toshiyuki, Ikeda Eiji, Ikenaka Kazuhiro

Neuroscience Letters 407 （ 2 ） 127 - 130 2006年10月

ISSN 0304-3940

Rosenthal fibers are homogeneous eosinophilic masses found in astrocytes that are composed of glial fibrillary acidic protein (GFAP) aggregates along with chaperone proteins and other unknown components. Rosenthal fiber formation is a pathological hallmark of Alexander disease and its detection is diagnostically significant. However, the lack of a specific fluorescent marker has greatly limited the histochemical characterization of Rosenthal fibers. Here, we report for the first time a fluorescent marker of Rosenthal fibers called Fluoro Jade. Fluoro Jade-positive masses were seen in samples of Alexander disease brain, pilocytic astrocytoma, and in brain tissue from a mouse model of Alexander disease. Fluoro Jade co-labeled tissue samples stained with GFAP immunofluorescence. Our results indicated that Fluoro Jade labeled Rosenthal fibers, and that Rosenthal fibers could be labeled with antibodies of interest in combination with Fluoro Jade staining. © 2006 Elsevier Ireland Ltd. All rights reserved.

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An animal model for late onset chronic demyelination disease caused by failed terminal differentiation of oligodendrocytes

Ma Jianmei, Matsumoto Michio, Tanaka Kenji F., Takebayashi Hirohide, Ikenaka Kazuhiro

Neuron Glia Biology 2 （ 2 ） 81 - 91 2006年05月

ISSN 1740-925X

Various animal models are available for studying human multiple sclerosis (MS). Most of them model the initial phase of MS, including the immune-triggered attack of the myelin membrane and/or oligodendrocytes and, occasionally, demonstrate the remission and relapsing phases. However, few mimic the late chronic demyelinating phase. Overexpression of the proteolipid protein gene (Plp) causes a unique demyelinating disorder in mice in which normal-appearing myelin forms early in life and chronic demyelination occurs later. We found that remyelination is severely affected in this late demyelinating phase, but is not caused by deprivation of oligodendrocyte progenitors expressing PDGF receptor alpha (PDGFRα) and Olig2, which are present at an even higher number in the demyelinated white matter of the mutants than in wild-type controls. Furthermore, mature oligodendrocytes containing PLP were observed, but failed to remyelinate. The ability of oligodendrocytes from older transgenic animals to produce a myelin membrane-like structure was not impaired when cultured in vitro, which indicates that the lack of remyelination is not simply caused by changes in the intrinsic properties of the oligodendrocytes. Glial activation also occurred much earlier than active demyelination in mutant mice. Thus, in addition to intrinsic mechanisms, extrinsic mechanisms might also have an important role in defects of remyelination. These features are also observed in patients at a late stage of MS, leading to chronic demyelinating lesions. Thus, this mouse model partly mimics the late stage of MS and can be used to study the cause of inhibition of remyelination. © 2005 Cambridge University Press.

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Short-term lineage analysis of dorsally derived Olig3 cells in the developing spinal cord

Ding Lei, Takebayashi Hirohide, Watanabe Keisuke, Ohtsuki Toshiaki, Tanaka Kenji F., Nabeshima Yo Ichi, Chisaka Osamu, Ikenaka Kazuhiro, Ono Katsuhiko

Developmental Dynamics 234 （ 3 ） 622 - 632 2005年11月

ISSN 1058-8388

We examined the migration and differentiation of cells expressing Olig3, a basic helix-loop-helix transcriptional factor, in the developing spinal cord. Distribution of Olig3 lineage cells was demonstrated with in situ hybridization and X-gal staining in an Olig3-lacZ knock-in mouse. Olig3-positive cells first appeared in the dorsal spinal cord, except for the roof plate. Some of the dorsal Olig3 lineage cells co-expressed Islet1/2, Math1, or Brn3a, markers for dorsal interneuron. LacZ-positive cells were observed in the ventral-most part of the E10.5 spinal cord, suggesting that some dorsal Olig3 lineage cells migrate into the ventral-most part by E10.5. Ventral-ward migration of dorsal cells and contribution to commissural interneurons were substantiated by electroporation of EGFP expression plasmid in the dorsal spinal cord of chick embryo. Dorsal midline cells were also LacZ-positive during development. These findings suggest that dorsal Olig3 cells contribute to dorsal midline cells and commissural interneurons at intermediate and ventral levels. © 2005 Wiley-Liss, Inc.

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Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia

Suzuki Takefumi, Uchida Hiroyuki, Tanaka Kenji F., Nomura Kensuke, Takano Harumasa, Tanabe Akira, Watanabe Koichiro, Yagi Gohei, Kashima Haruo

International Journal of Neuropsychopharmacology 7 （ 2 ） 133 - 142 2004年06月

ISSN 1461-1457

Antipsychotic polypharmacy has been empirically used and a recent trend in favour of that mode of therapy has been suggested for the treatment of schizophrenia. The clinical efficacy, however, still remains to be clarified. In order to critically evaluate the usefulness of such kind of psychopharmacotherapy, antipsychotic combination regimen (polypharmacy) was switched to a treatment with the single main antipsychotic (monotherapy) in cross-tapered fashion, while approximately maintaining the total amount, for patients with chronic schizophrenia. Patients had been treated with an average of three antipsychotics and maintained with the same antipsychotic polypharmacy regimen for more than 6 months before the entry. They were followed up with an antipsychotic monopharmacy and evaluated at 24 wk after completion of switching. Forty-seven patients were recruited for this study. Of 44 patients for whom evaluation was possible, 24 (54.5%) remained stable, while 10 (22.7%) showed improvement and the same number of patients ended in a deleterious status. Twenty-two patients were converted to antipsychotic monotherapy, while another 12 needed minimal dosing of low-potency agents. Overall, social functioning, evaluated by the Global Assessment of Functioning and the Clinical Global Impression, remained unchanged. Eighteen of 34 successful patients showed adverse effects of the main antipsychotic medication, which necessitated a significant dose reduction. Nine out of 10 deteriorating patients had been treated with a combination of low- and high-potency antipsychotics. It is suggested that many instances of antipsychotic polypharmacy is avoidable. The result is compatible with the current treatment recommendations, which dictate the use of a single antipsychotic agent.

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Reducing the dose of antipsychotic medications for those who had been treated with high-dose antipsychotic polypharmacy

Suzuki Takefumi, Uchida Hiroyuki, Tanaka Kenji F., Tomita Masayuki, Tsunoda Kenichi, Nomura Kensuke, Takano Harumasa, Tanabe Akira, Watanabe Koichiro, Yagi Gohei, Kashima Haruo

International Clinical Psychopharmacology 18 （ 6 ） 323 - 329 2003年11月

ISSN 0268-1315

Antipsychotic medications are often used at higher than the recommended dose and sometimes in a combination regimen to treat schizophrenia. However, in general, high-dose therapies have been abandoned in recent clinical studies. In this study, dose reduction of antipsychotic medication was implemented for patients with chronic schizophrenia, most of whom (81%) had been treated with an antipsychotic high-dose polypharmacy regimen consisting of more than 1000 mg/day in total amount. The results show that merely reducing the amount of antipsychotic led to favourable outcome in 23 out of 41 cases (56%), with another 13 cases (32%) showing no change. Dose reduction ended in failure in only five subjects (12%). Overall, the amount as well as the number of antipsychotic medications was significantly reduced from 1984 mg to 812 mg per day (reductions of 59% and from 3.6 to 2.2, respectively; both P<0.0001). The Global Assessment of Functioning scale improved from 30.6 to 37.2, which reached significance (P<0.001). Accordingly, the Severity of Illness improved from 4.7 to 4.2, and was also significant (P<0.01). Dose reduction is an encouraging strategy to consider for those patients with schizophrenia who have chronically been treated with high-dose antipsychotic polypharmacy, even if judged unavoidable in the past. © 2003 Lippincott Williams & Wilkins.

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