論文 - 田中　謙二

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

　概要を見る

<p>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.</p>

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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

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<p>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.</p>

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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

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<p>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.</p>

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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

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<p>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.</p>

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Challenge to understand the neurobiology of obsessive-compulsive disorder

Tanaka Kenji

Brain and Nerve 64 （ 8 ） 903 - 909 2012年08月

ISSN  1881-6096

　概要を見る

<p>Obsessive-compulsive disorder (OCD) is characterized by obsession (recurrent intrusive thoughts) and compulsion (repetitive behaviors or mental acts). There is no consensus regarding the pathogenesis of OCD, which could support the idea that this disorder is heterogeneous. However, functional imaging data and surgical findings in humans suggest that the hyperactivity of the specific circuit including the striatum, called the cortico-striato-thalamo- cortical circuit, plays a role in OCD pathogenesis. Recently, validated animal models of OCD have been established, and they provide us the opportunity to address how the altered functional activity of this circuit contributes to the repetitive behavior in OCD. To test the causal relationship between the altered function of the circuit and behavioral abnormalities in animals, cell-type-specific manipulation and detection of changes in the circuit will be required. Optogenetic approaches may be used as tools to dissect the complex circuit. Moreover, mouse functional magnetic resonance imaging may yield data comparable to human imaging data.</p>

Gene induction in mature oligodendrocytes with a PLP-tTA mouse line

Inamura Naoko, Sugio Shouta, Macklin Wendy B., Tomita Koichi, Tanaka Kenji F., Ikenaka Kazuhiro

Genesis 50 （ 5 ） 424 - 428 2012年05月

ISSN  1526-954X

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<p>Mature oligodendrocytes are critical for myelin maintenance. To understand the molecular basis for this, genetic manipulation of mature oligodendrocytes is needed. Here we generated a mature oligodendrocyte tTA (tetracycline-controlled transcriptional activator) mouse line which, in combination with a tTA-dependent promoter line driving the expression of the desired transgene, can be used for gain-of-function studies. We used an oligodendrocyte promoter, the mouse proteolipid protein (PLP) promoter, to express mammalianized tTA, and generated a PLP-mtTA mouse line. In adults, mtTA mRNA was predominantly detected in brain white matter where it co-localized with PLP mRNA. mtTA-mediated gene induction was confirmed by crossing to mice with a tTA-dependent promoter driving expression of yellow fluorescent protein (tetO-YFP mice). YFP induction in PLP-mtTA::tetO-YFP mice was consistent with PLP expression in adult mature oligodendrocytes and premyelinating-stage myelinating oligodendrocytes. This PLP-mtTA mouse line is the first to enable gain-of-function studies in mature oligodendrocytes with the tet system. © 2011 Wiley Periodicals, Inc.</p>

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Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path

Gire David H., Franks Kevin M., Zak Joseph D., Tanaka Kenji F., Whitesell Jennifer D., Mulligan Abigail A., Hen René, Schoppa Nathan E.

Journal of Neuroscience 32 （ 9 ） 2964 - 2975 2012年02月

ISSN  0270-6474

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<p>Within the olfactory system, information flow from the periphery onto output mitral cells (MCs) of the olfactory bulb (OB) has been thought to be mediated by direct synaptic inputs from olfactory sensory neurons (OSNs). Here, we performed patch-clamp measurements in rat and mouse OB slices to investigate mechanisms of OSN signaling onto MCs, including the assumption of a direct path, using electrical and optogenetic stimulation methods that selectively activated OSNs. We found that MCs are in fact not typically activated by direct OSN inputs and instead require a multistep, diffuse mechanism involving another glutamatergic cell type, the tufted cells. The preference for a multistep mechanism reflects the fact that signals arising from direct OSN inputs are drastically shunted by connexin 36-mediated gap junctions on MCs, but not tufted cells. An OB circuit with tufted cells intermediate between OSNs and MCs suggests that considerable processing of olfactory information occurs before its reaching MCs. © 2012 the authors.</p>

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Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path.

田中 謙二

J Neurosci. 32   2964 - 2975 2012年

研究論文（学術雑誌）, 査読有り

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

田中 謙二

Proc Natl Acad Sci U S A 109   20720 - 20725 2012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.

田中 謙二

PLoS One 7   e52783 2012年

査読有り

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Preinspiratory calcium rise in putative pre-Botzinger complex astrocytes.

田中 謙二

J Physiol 590   4933 - 4944 2012年

共著, 査読有り

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Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism.

田中 謙二

Science 338   128 - 132 2012年

研究論文（学術雑誌）, 共著, 査読有り

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

田中 謙二

Philos Trans R Soc Lond B Biol Sci 367   2395 - 2401 2012年

研究論文（学術雑誌）, 共著, 査読有り

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

田中 謙二

Cell Rep 2   397 - 406 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Gene induction in mature oligodendrocytes with a PLP-tTA mouse line.

田中 謙二

Genesis 50   424 - 428 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells

Hitoshi Seiji, Ishino Yugo, Kumar Akhilesh, Jasmine Salma, Tanaka Kenji F., Kondo Takeshi, Kato Shigeaki, Hosoya Toshihiko, Hotta Yoshiki, Ikenaka Kazuhiro

Nature Neuroscience 14 （ 8 ） 957 - 964 2011年08月

ISSN  1097-6256

　概要を見る

<p>Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 anD₂) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1 ^-/-; Gcm2 ^-/- mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway. © 2011 Nature America, Inc. All rights reserved.</p>

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Microglial cystatin F expression is a sensitive indicator for ongoing demyelination with concurrent remyelination

Ma Jianmei, Tanaka Kenji F., Shimizu Takahiro, Bernard Claude C A, Kakita Akiyoshi, Takahashi Hitoshi, Pfeiffer Steven E., Ikenaka Kazuhiro

Journal of Neuroscience Research 89 （ 5 ） 639 - 649 2011年05月

ISSN  0360-4012

　概要を見る

<p>Demyelination coincides with numerous changes of gene expression in the central nervous system (CNS). Cystatin F, which is a papain-like lysosomal cysteine proteinase inhibitor that is normally expressed by immune cells and not in the brain, is massively induced in the CNS during acute demyelination. We found that microglia, which are monocyte/macrophage-lineage cells in the CNS, express cystatin F only during demyelination. By using several demyelinating animal models and the spinal cord tissues from multiple sclerosis (MS) patients, we examined spatiotemporal expression pattern of cystatin F by in situ hybridization and immunohistochemistry. We found that the timing of cystatin F induction matches with ongoing demyelination, and the places with cystatin F expression overlapped with the remyelinating area. Most interestingly, cystatin F induction ceased in chronic demyelination, in which remyelinating ability was lost. These findings demonstrate that the expression of cystatin F indicates the occurrence of ongoing demyelination/remyelination and the absence of cystatin F expression indicates the cessation of remyelination in the demyelinating area. © 2011 Wiley-Liss, Inc.</p>

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Leptin-dependent serotonin control of appetite

Yadav Vijay K., Oury Franck, Tanaka Kenji F., Thomas Tiffany, Wang Ying, Cremers Serge, Hen Rene, Krust Andree, Chambon Pierre, Karsenty Gerard

Journal of Experimental Medicine 208 （ 2 ） 413 2011年02月

ISSN  0022-1007

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Functional connectome of the striatal medium spiny neuron

Chuhma Nao, Tanaka Kenji F., Hen René, Rayport Stephen

Journal of Neuroscience 31 （ 4 ） 1183 - 1192 2011年01月

ISSN  0270-6474

　概要を見る

<p>Dopamine system disorders ranging from movement disorders to addiction and schizophrenia involve striatal medium spiny neurons (MSNs), yet their functional connectivity has been difficult to determine comprehensively. We generated a mouse with conditional channelrhodopsin-2 expression restricted to medium spiny neurons and assessed the specificity and strength of their intrinsic connections in the striatum and their projections to the globus pallidus and the substantia nigra. In the striatum, medium spiny neurons connected with other MSNs and tonically active cholinergic interneurons, but not with fast-spiking GABA interneurons. In the globus pallidus, medium spiny neurons connected strongly with one class of electrophysiologically identified neurons, but weakly with the other. In the substantia nigra, medium spiny neurons connected strongly with GABA, but not with dopamine neurons. Projections to the globus pallidus showed solely D2-mediated presynaptic inhibition, whereas projections to the substantia nigra showed solely D1-mediated presynaptic facilitation. This optogenetic approach defines the functional connectome of the striatal medium spiny neuron. Copyright © 2011 the authors.</p>

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Leptin-dependent serotonin control of appetite

Yadav Vijay K., Oury Franck, Tanaka Kenji, Thomas Tiffany, Wang Ying, Cremers Serge, Hen Rene, Krust Andree, Chambon Pierre, Karsenty Gerard

Journal of Experimental Medicine 208 （ 1 ） 41 - 52 2011年01月

ISSN  0022-1007

　概要を見る

<p>Recent evidence indicates that leptin regulates appetite and energy expenditure, at least in part by inhibiting serotonin synthesis and release from brainstem neurons. To demonstrate that this pathway works postnatally, we used a conditional, brainstem-specific mouse CreER^T2 driver to show that leptin signals in brainstem neurons after birth to decrease appetite by inhibiting serotonin synthesis. Cell-specific gene deletion experiments and intracerebroventricular leptin infusions reveal that serotonin signals in arcuate nuclei of the hypothalamus through the Htr1a receptor to favor food intake and that this serotonin function requires the expression of Creb, which regulates the expression of several genes affecting appetite. Accordingly, a specific antagonist of the Htr1a receptor decreases food intake in leptin-deficient but not in Htr1a^-/- mice. Collectively, these results establish that leptin inhibition of serotonin is necessary to inhibit appetite postnatally and provide a proof of principle that selective inhibition of this pathway may be a viable option to treat appetite disorders. © 2011 Yadav et al.</p>

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