研究者詳細 - 田中　謙二

論文 - 田中　謙二

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Increased adenosine levels in mice expressing mutant glial fibrillary acidic protein in astrocytes result in failure of induction of LTP reversal (depotentiation) in hippocampal CA1 neurons

Fujii Satoshi, Tanaka Kenji F., Ikenaka Kazuhiro, Yamazaki Yoshihiko

Brain Research 1578 （ 1 ） 1 - 13 2014年

ISSN 0006-8993

Astrocytes regulate the activity of neighboring neurons by releasing chemical transmitters, including ATP. Adenosine levels in the cerebrospinal fluidof mice thatexpress amutanthuman glial fibrillary acidic protein in astrocytes are slightly elevated compared to those in wild type mice and this might result from the observed increased release by mutant astrocytes of ATP, which can be used to produce adenosine. Using hippocampal slices from these mutant mice, we examined whether the increased endogenous adenosine levels in the hippocampus modulate the reversal of long-term potentiation (LTP), i.e. depotentiation (DP), in CA1 neurons. In hippocampal slices from wild type mice, a stable LTP was induced by tetanic stimulation consisting of 100 pulses at 100 Hz, and this was reversed by a train of low frequency stimulation (LFS) of 500 pulses at 1 Hz applied 30 min later. This induction of DP was inhibited by application of either 100 nM adenosine or 0.5 nM N⁶-cyclopentyladenosine, an adenosine A₁ receptor agonist, during LFS, indicating that the increase in extracellular adenosine levels attenuated DP induction by acting on adenosine A1 receptors. In contrast, although a stable LTP was also induced in hippocampal slices from mutant mice, induction of DP was inhibited, but DP could be induced by application, during LFS, of 50 nM 8-cyclopentyltheophylline, an adenosine A1 receptor antagonist. These results suggest that a small increase in extracellular adenosine levels resulting from increased ATP release by astrocytes resultsinattenuationofDPinhippocampal CA1neurons inthemutantmice.

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Long-lasting silencing of orexin/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice

Tsunematsu Tomomi, Tabuchi Sawako, Tanaka Kenji F., Boyden Edward S., Tominaga Makoto, Yamanaka Akihiro

Behavioural Brain Research 255 64 - 74 2013年10月

ISSN 0166-4328

Orexin/hypocretin neurons have a crucial role in the regulation of sleep and wakefulness. Recent optogenetic studies revealed that the activation or inhibition of orexin neuronal activity affects the probability of sleep/wakefulness transition in the acute phase. To expand our understanding of how orexin neurons maintain wakefulness, we generated new transgenic mice in which orexin neurons expressed archaerhodopsin from Halorubrum strain TP009 (ArchT), a green light-driven neuronal silencer, using the tet-off system (orexin-tTA; TetO ArchT mice). Slice patch clamp recordings of ArchT-expressing orexin neurons demonstrated that long-lasting photic illumination was able to silence the activity of orexin neurons. We further confirmed that green light illumination for 1. h in the dark period suppressed orexin neuronal activity in vivo using c-Fos expression. Continuous 1. h silencing of orexin neurons in freely moving orexin-tTA; TetO ArchT mice during the night (the active period, 20:00-21:00) significantly increased total time spent in slow-wave sleep (SWS) and decreased total wake time. Additionally, photic inhibition increased sleep/wakefulness state transitions, which is also evident in animals lacking the prepro-orexin gene, orexin neurons, or functional orexin-2 receptors. However, continuous 1. h photic illumination produced little effect on sleep/wakefulness states during the day (the inactive period, 12:00-13:00). These results suggest that orexin neuronal activity plays a crucial role in the maintenance of wakefulness especially in the active phase in mice. © 2013 The Authors.

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Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness

Tabuchi Sawako, Tsunematsu Tomomi, Kilduff Thomas S., Sugio Shouta, Xu Ming, Tanaka Kenji F., Takahashi Satoru, Tominaga Makoto, Yamanaka Akihiro

Sleep 36 （ 9 ） 1391 - 1404 2013年09月

ISSN 0161-8105

Study Objective: Serotonergic (5HT) neurons of the dorsal raphe nuclei receive excitatory input from hypothalamic orexin (hypocretin) neurons and reciprocally inhibit orexin neurons through the 5HT1A receptor. However, the physiological significance of this negative feedback circuit for sleep/wakefulness regulation is little understood. Design: 5HT1A receptor expression level was specifically and reversibly controlled in the orexin neurons using the Tet-off system. The responsiveness of orexin neurons to 5HT in vitro and the sleep/wakefulness patterns were compared between 5HT1A-overexpressing and control mice. Measurements and Results: When the 5HT1A receptor was overexpressed in orexin neurons of Orexin-EGFP; orexin-tTA; TetO Htr1a mice, 5HTinduced inhibition of orexin neurons was prolonged. In the absence of doxycycline, Orexin-tTA; TetO Htr1a mice exhibited severe fragmentation of sleep/wakefulness during the first half of the dark period-the time of maximal activity in nocturnal rodents-without affecting sleep/wakefulness during the light period when sleep time is maximal. However, when the 5HT1A receptor in orexin neurons was reduced to basal expression levels in the presence of doxycycline, sleep/wakefulness patterns in Orexin-tTA; TetO Htr1a mice during the early active period were indistinguishable from those of littermate TetO Htr1a mice. These results strongly suggest that enhancement of inhibitory serotonergic input to orexin neurons caused fragmentation of wakefulness. In contrast, sleep/wakefulness architecture in the light period was unaffected by 5HT1A receptor overexpression in the orexin neurons. Conclusion: Inhibitory serotonergic input likely functions as negative feedback to orexin neurons in the early dark period and helps stabilize wakefulness bouts, thereby contributing to the diurnal rhythm of sleep and wakefulness. © 2013 Associated Professional Sleep Societies, LLC.

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Increased astrocytic ATP release results in enhanced excitability of the hippocampus

Lee Hae Ung, Yamazaki Yoshihiko, Tanaka Kenji F., Furuya Kishio, Sokabe Masahiro, Hida Hideki, Takao Keizo, Miyakawa Tsuyoshi, Fujii Satoshi, Ikenaka Kazuhiro

GLIA 61 （ 2 ） 210 - 224 2013年02月

ISSN 0894-1491

Astrocytes, a major subtype of glia, interact with neurons as a supportive partner supplying energy sources and growth factors. Astrocytes regulate the activity of neighboring neurons by releasing chemical transmitters (gliotransmitters). However, the precise role of gilotransmitters in regulating neuronal activity is still under debate. Here, we report that a subtle enhancement in the release of one gliotransmitter, ATP, affects synaptic potentiation from an analysis of mice containing an astrocyte-selective (GFAP) mutation. We found that, relative to normal mice, weaker stimulation induced long-term potentiation (LTP) in mutant mice, indicating that the threshold to induce LTP was lowered in the mutant. While excitatory transmission was normal in the mutant, inhibitory GABAergic transmission was suppressed. We found that a low concentration of adenosine selectively attenuated inhibitory neuronal activity and lowered the threshold to induce LTP in wild type mice. In comparison, adenosine A₁ receptor antagonism reversed the lowered LTP threshold back to normal in the mutant mouse. We verified that adenosine levels in the cerebrospinal fluid of mutant mice were slightly elevated compared to wild type mice. This was apparently caused by an increase in ATP release from mutant astrocytes that could provide a source of augmented adenosine levels in the mutant. ATP is thought to suppress the excitability of neuronal circuits; however, a small increase in ATP release can result in a suppressed inhibitory tone and enhanced excitability of neuronal circuitry. These findings demonstrate that ATP released from astrocytes acts in a bidirectional fashion to regulate neuronal excitability depending on concentration. © 2012 Wiley Periodicals, Inc.

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Olig2-lineage cells preferentially differentiate into oligodendrocytes but their processes degenerate at the chronic demyelinating stage of proteolipid protein-overexpressing mouse

Shimizu Takahiro, Tanaka Kenji F., Takebayashi Hirohide, Higashi Mikito, Wisesmith Wilaiwan, Ono Katsuhiko, Hitoshi Seiji, Ikenaka Kazuhiro

Journal of Neuroscience Research 91 （ 2 ） 178 - 186 2013年02月

ISSN 0360-4012

In chronic demyelinating lesions of the central nervous system, insufficient generation of oligodendrocytes (OLs) is not due to a lack of oligodendrocyte precursor cells (OPCs), because the accumulation of OPCs and premyelinating OLs can be observed within these lesions. Here we sought to identify the basis for the failure of OLs to achieve terminal differentiation in chronic demyelinating lesions through the utilization of plp1-overexpressing (Plp^tg/-) mice. These mice are characterized by progressive demyelination in young adults and chronic demyelinating lesions at more mature stages. We show that neural stem cells, which are the precursors of OL-lineage cells, are present in the Plp^tg/- mouse brain and that their multipotentiality and ability to self-renew are comparable to those of wild-type adults in culture. Lineage-tracing experiments using a transgenic mouse line, in which an inducible Cre recombinase is knocked in at the Olig2 locus, revealed that Olig2-lineage cells preferentially differentiated into OPCs and premyelinating OLs, but not into astrocytes, in the Plp^tg/- mouse brain. These Olig2-lineage cells matured to express myelin basic protein but after that their processes degenerated in the chronic demyelinating lesions of the Plp^tg/- brain. These results indicate that in chronic demyelinated lesions more OL-lineage cells are produced as part of the repair process, but their processes degenerate after maturation. © 2012 Wiley Periodicals, Inc.

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The manipulation of neural and cellular activities by ectopic expression of melanopsin

Koizumi Amane, Tanaka Kenji F., Yamanaka Akihiro

Neuroscience Research 75 （ 1 ） 3 - 5 2013年01月

ISSN 0168-0102

Melanopsin (OPN4) is a photosensitive pigment originally found in a subtype of retinal ganglion cells and is a 7-transmembrane G-protein-coupled receptor (GPCR). Several previous reports showed that ectopic expression of OPN4 can be used as an optogenetic tool to control neural and cellular activities in various tissues. Compared with other optogenetic pigments, OPN4 is more sensitive to light, shows long-lasting activation, and can also control intracellular Ca²⁺ dynamics. Here, we review how the ectopic expression of OPN4 enables the control of neural and cellular activities in vivo. In the retina, the ectopic expression of melanopsin in retinal ganglion cells successfully restored the vision of blind mice. It has also been reported that ectopic expression of melanopsin in orexin/hypocretin neurons enabled control of wakefulness in mice by blue light. In addition to neural activity, the ectopic expression of OPN4 has been reported to enable circuit control of the nuclear factor of activated T cells (NFAT) to enhance blood-glucose homeostasis in mice. We discuss the possibility of optogenetic control of other systems through the ectopic expression of OPN4. © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Ectopic expression of melanopsin in orexin/hypocretin neurons enables control of wakefulness of mice in vivo by blue light

Tsunematsu Tomomi, Tanaka Kenji F., Yamanaka Akihiro, Koizumi Amane

Neuroscience Research 75 （ 1 ） 23 - 28 2013年01月

ISSN 0168-0102

Melanopsin (OPN4) is a photosensitive G-protein-coupled photopigment and its ectopic expression enables control of neural activity induced by blue light. Here we report that we successfully expressed OPN4 in hypothalamic orexin/hypocretin neurons of double-transgenic mice (orexin-tTA; Bitet-O human OPN4 [hOPN4]/mCherry mice). In the double-transgenic mice, hypothalamic orexin neurons selectively expressed hOPN4 as well as mCherry as a reporter. We conducted slice patch-clamp recordings on hOPN4/mCherry-expressing orexin neurons, which showed long-lasting activation initiated by blue light even after the light was switched off. Optical fiber-guided blue light stimulation in the hypothalamus successfully initiated the electroencephalography pattern that reflects long-lasting wakefulness in the mice in vivo. Taken together, the results indicate that ectopic expression of hOPN4 in orexin neurons enables long-lasting activation of orexin neurons by blue light to control sleep/wakefulness of the mice. © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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[Optogenetics in biological psychiatry].

Tanaka Kenji F., Takata Norio, Mimura Masaru

Unknown Journal 115 （ 12 ） 1211 - 1215 2013年

The manipulation of neural and cellular activities by ectopic expression of melanopsin.

田中謙二

Neurosci　Res. 75 3 - 5 2013年

研究論文（学術雑誌）, 共著, 査読有り

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Ectopic expression of melanopsin in orexin/hypocretin neurons enables control of wakefulness of mice in vivo by blue light.

田中謙二

Neurosci Res. 75 23 - 28 2013年

研究論文（学術雑誌）, 共著, 査読有り

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Olig2-lineage cells preferentially differentiate into oligodendrocytes but their processes degenerate at the chronic demyelinating stage of proteolipid protein-overexpressing mouse.

田中謙二

J Neurosci Res. 91 178 - 186 2013年

研究論文（学術雑誌）, 共著, 査読有り

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Increased astrocytic ATP release results in enhanced excitability of the hippocampus.

田中謙二

Glia. 61 210 - 214 2013年

研究論文（学術雑誌）, 共著, 査読有り

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Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness.

田中謙二

Sleep. 36 1391 - 1404 2013年

研究論文（学術雑誌）, 共著

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Long-lasting silencing of orexin/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice.

田中謙二

Behav Brain Res. 255 64 - 74 2013年

研究論文（学術雑誌）, 共著, 査読有り

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Identification of Optogenetically Activated Striatal Medium Spiny Neurons by Npas4 Expression

Bepari Asim K., Sano Hiromi, Tamamaki Nobuaki, Nambu Atsushi, Tanaka Kenji F., Takebayashi Hirohide

PLoS One 7 （ 12 ） 2012年12月

ISSN 1932-6203

Optogenetics is a powerful neuromodulatory tool with many unique advantages to explore functions of neuronal circuits in physiology and diseases. Yet, interpretation of cellular and behavioral responses following in vivo optogenetic manipulation of brain activities in experimental animals often necessitates identification of photoactivated neurons with high spatial resolution. Although tracing expression of immediate early genes (IEGs) provides a convenient approach, neuronal activation is not always followed by specific induction of widely used neuronal activity markers like c-fos, Egr1 and Arc. In this study we performed unilateral optogenetic stimulation of the striatum in freely moving transgenic mice that expressed a channelrhodopsin-2 (ChR2) variant ChR2(C128S) in striatal medium spiny neurons (MSNs). We found that in vivo blue light stimulation significantly altered electrophysiological activity of striatal neurons and animal behaviors. To identify photoactivated neurons we then analyzed IEG expression patterns using in situ hybridization. Upon light illumination an induction of c-fos was not apparent whereas another neuronal IEG Npas4 was robustly induced in MSNs ipsilaterally. Our results demonstrate that tracing Npas4 mRNA expression following in vivo optogenetic modulation can be an effective tool for reliable and sensitive identification of activated MSNs in the mouse striatum. © 2012 Bepari et al.

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Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation.

Sasaki Takuya, Beppu Kaoru, Tanaka Kenji F., Fukazawa Yugo, Shigemoto Ryuichi, Matsui K.

Proceedings of the National Academy of Sciences of the United States of America 109 （ 50 ） 20720 - 20725 2012年12月

ISSN 0027-8424

Dynamic activity of glia has repeatedly been demonstrated, but if such activity is independent from neuronal activity, glia would not have any role in the information processing in the brain or in the generation of animal behavior. Evidence for neurons communicating with glia is solid, but the signaling pathway leading back from glial-to-neuronal activity was often difficult to study. Here, we introduced a transgenic mouse line in which channelrhodopsin-2, a light-gated cation channel, was expressed in astrocytes. Selective photostimulation of these astrocytes in vivo triggered neuronal activation. Using slice preparations, we show that glial photostimulation leads to release of glutamate, which was sufficient to activate AMPA receptors on Purkinje cells and to induce long-term depression of parallel fiber-to-Purkinje cell synapses through activation of metabotropic glutamate receptors. In contrast to neuronal synaptic vesicular release, glial activation likely causes preferential activation of extrasynaptic receptors that appose glial membrane. Finally, we show that neuronal activation by glial stimulation can lead to perturbation of cerebellar modulated motor behavior. These findings demonstrate that glia can modulate the tone of neuronal activity and behavior. This animal model is expected to be a potentially powerful approach to study the role of glia in brain function.

Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism

Baudouin Stéphane J., Gaudias Julien, Gerharz Stefan, Hatstatt Laetitia, Zhou Kuikui, Punnakkal Pradeep, Tanaka Kenji F., Spooren Will, Hen Rene, De Zeeuw Chris I., Vogt Kaspar, Scheiffele Peter

Science 338 （ 6103 ） 128 - 132 2012年10月

ISSN 0036-8075

The genetic heterogeneity of autism poses a major challenge for identifying mechanism-based treatments. A number of rare mutations are associated with autism, and it is unclear whether these result in common neuronal alterations. Monogenic syndromes, such as fragile X, include autism as one of their multifaceted symptoms and have revealed specific defects in synaptic plasticity. We discovered an unexpected convergence of synaptic pathophysiology in a nonsyndromic form of autism with those in fragile X syndrome. Neuroligin-3 knockout mice (a model for nonsyndromic autism) exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor - dependent synaptic plasticity, a hallmark of fragile X. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development.

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Preinspiratory calcium rise in putative pre-Bötzinger complex astrocytes

Okada Yasumasa, Sasaki Takuya, Oku Yoshitaka, Takahashi Naoya, Seki Megumi, Ujita Sakiko, Tanaka Kenji F., Matsuki Norio, Ikegaya Yuji

Journal of Physiology 590 （ 19 ） 4933 - 4944 2012年10月

ISSN 0022-3751

The neural inspiratory activity originates from a ventrolateral medullary region called the pre-Bötzinger complex (preBötC), yet the mechanism underlying respiratory rhythmogenesis is not completely understood. Recently, the role of not only neurons but astrocytes in the central respiratory control has attracted considerable attention. Here we report our discovery that an intracellular calcium rise in a subset of putative astrocytes precedes inspiratory neuronal firing in rhythmically active slices. Functional calcium imaging from hundreds of preBötC cells revealed that a subset of putative astrocytes exhibited rhythmic calcium elevations preceding inspiratory neuronal activity with a time lag of approximately 2 s. These preinspiratory putative astrocytes maintained their rhythmic activities even during the blockade of neuronal activity with tetrodotoxin, whereas the rhythm frequency was lowered and the intercellular phases of these rhythms were decoupled. In addition, optogenetic stimulation of preBötC putative astrocytes induced firing of inspiratory neurons. These findings raise the possibility that astrocytes in the preBötC are actively involved in respiratory rhythm generation in rhythmically active slices. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.

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Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus

Tanaka Kenji F., Samuels Benjamin Adam, Hen René

Philosophical Transactions of the Royal Society B: Biological Sciences 367 （ 1601 ） 2395 - 2401 2012年09月

ISSN 0962-8436

Using in situ hybridization, we describe, for the first time, the profiles of expression of serotonin receptors (Htr/5-HTR) along the dorsal-ventral axis of mouse hippocampus. cRNA probes for most Htrs, excluding Htr6, were used. All hippocampal subregions and the entorhinal cortex cells providing input into the hippocampus were examined. The study shows that some, but not all, Htrs are expressed in the cells of the hippocampal circuitry. At both the subfield and the cell type levels, a somewhat overlapping pattern is observed. Four serotonin receptors, Htr1a, Htr2a, Htr2c and Htr7, display an expression pattern that changes along the dorsal-ventral axis of the hippocampus. Given the proposed functional differentiation of the hippocampus along its long axis, with the dorsal pole more involved in cognitive functions and the ventral pole more involved in mood and anxiety, our results suggest that serotonin receptors enriched in the ventral pole probably contribute to mood- and anxiety-related behaviours. © 2012 The Royal Society.

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Expanding the Repertoire of Optogenetically Targeted Cells with an Enhanced Gene Expression System

Tanaka Kenji F., Matsui Ko, Sasaki Takuya, Sano Hiromi, Sugio Shouta, Fan Kai, Hen René, Nakai Junichi, Yanagawa Yuchio, Hasuwa Hidetoshi, Okabe Masaru, Deisseroth Karl, Ikenaka Kazuhiro, Yamanaka Akihiro

Cell Reports 2 （ 2 ） 397 - 406 2012年08月

Drosophila neuroblasts (NBs) have emerged as a model for stem cell biology that is ideal for genetic analysis but is limited by the lack of cell-type-specific gene expression data. Here, we describe a method for isolating large numbers of pure NBs and differentiating neurons that retain both cell-cycle and lineage characteristics. We determine transcriptional profiles by mRNA sequencing and identify 28 predicted NB-specific transcription factors that can be arranged in a network containing hubs for Notch signaling, growth control, and chromatin regulation. Overexpression and RNA interference for these factors identify Klumpfuss as a regulator of self-renewal. We show that loss of Klumpfuss function causes premature differentiation and that overexpression results in the formation of transplantable brain tumors. Our data represent a valuable resource for investigating Drosophila developmental neurobiology, and the described method can be applied to other invertebrate stem cell lineages as well.

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田中 謙二

論文 - 田中 謙二

田中　謙二

論文 - 田中　謙二