石田 綾 (イシダ アヤ)

Ishida, Aya

写真a

所属(所属キャンパス)

医学部 生理学教室 (信濃町)

職名

専任講師(有期)

 

研究分野 【 表示 / 非表示

  • 生理学一般

研究キーワード 【 表示 / 非表示

  • レット症候群 シナプス 小脳

 

論文 【 表示 / 非表示

  • Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model

    H. Lu, R. T. Ash, L. He, S. E. Kee, W. Wang, D. Yu, S. Hao, X. Meng, K. Ure, A. Ito-Ishida, B. Tang, Y. Sun, D. Ji, J. Tang, B. R. Arenkiel, S. M. Smirnakis and H. Y. Zoghbi

    Neuron 91 ( 4 ) 739 - 747 2016年08月

    ISSN  1097-4199

     概要を見る

    Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice.

  • Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

    K. Ure, H. Lu, W. Wang, A. Ito-Ishida, Z. Wu, L. J. He, Y. Sztainberg, W. Chen, J. Tang and H. Y. Zoghbi

    Elife 5 2016年06月

    ISSN  2050-084X

     概要を見る

    The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

  • Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes

    A. Ito-Ishida, K. Ure, H. Chen, J. W. Swann and H. Y. Zoghbi

    Neuron 88 ( 4 ) 651 - 8 2015年11月

    ISSN  1097-4199

     概要を見る

    Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors.

  • The role of Cbln1 on Purkinje cell synapse formation

    A. Ito-Ishida, S. Okabe and M. Yuzaki

    Neurosci Res 83   64 - 8 2014年06月

    ISSN  1872-8111

     概要を見る

    Cbln1 is a glycoprotein which belongs to the C1q family. In the cerebellum, Cbln1 is produced and secreted from granule cells and works as a strong synapse organizer between Purkinje cells and parallel fibers, the axons of the granule cells. In this update article, we will describe the molecular mechanisms by which Cbln1 induces synapse formation and will review our findings on the axonal structural changes which occur specifically during this process. We will also describe our recent finding that Cbln1 has a suppressive role in inhibitory synapse formation between Purkinje cells and molecular layer interneurons. Our results have revealed that Cbln1 plays an essential role to establish parallel fiber-Purkinje cell synapses and to regulate balance between excitatory and inhibitory input on Purkinje cells.

  • Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells

    A. Ito-Ishida, W. Kakegawa, K. Kohda, E. Miura, S. Okabe and M. Yuzaki

    Eur J Neurosci 39 ( 8 ) 1268 - 80 2014年04月

    ISSN  1460-9568

     概要を見る

    The formation of excitatory and inhibitory synapses must be tightly coordinated to establish functional neuronal circuitry during development. In the cerebellum, the formation of excitatory synapses between parallel fibers and Purkinje cells is strongly induced by Cbln1, which is released from parallel fibers and binds to the postsynaptic delta2 glutamate receptor (GluD2). However, Cbln1's role, if any, in inhibitory synapse formation has been unknown. Here, we show that Cbln1 downregulates the formation and function of inhibitory synapses between Purkinje cells and interneurons. Immunohistochemical analyses with an anti-vesicular GABA transporter antibody revealed an increased density of interneuron-Purkinje cell synapses in the cbln1-null cerebellum. Whole-cell patch-clamp recordings from Purkinje cells showed that both the amplitude and frequency of miniature inhibitory postsynaptic currents were increased in cbln1-null cerebellar slices. A 3-h incubation with recombinant Cbln1 reversed the increased amplitude of inhibitory currents in Purkinje cells in acutely prepared cbln1-null slices. Furthermore, an 8-day incubation with recombinant Cbln1 reversed the increased interneuron-Purkinje cell synapse density in cultured cbln1-null slices. In contrast, recombinant Cbln1 did not affect cerebellar slices from mice lacking both Cbln1 and GluD2. Finally, we found that tyrosine phosphorylation was upregulated in the cbln1-null cerebellum, and acute inhibition of Src-family kinases suppressed the increased inhibitory postsynaptic currents in cbln1-null Purkinje cells. These findings indicate that Cbln1-GluD2 signaling inhibits the number and function of inhibitory synapses, and shifts the excitatory-inhibitory balance towards excitation in Purkinje cells. Cbln1's effect on inhibitory synaptic transmission is probably mediated by a tyrosine kinase pathway.

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競争的資金等の研究課題 【 表示 / 非表示

  • 発達障害の病態理解に向けた小脳-前頭前野-領野連関の解明

    2018年04月
    -
    2020年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 石田 綾, 新学術領域研究(研究領域提案型), 補助金,  代表

  • レット症候群における小脳神経回路異常の解明

    2017年08月
    -
    2019年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 石田 綾, 研究活動スタート支援, 補助金,  代表

受賞 【 表示 / 非表示

  • 日本神経科学会奨励賞

    2013年, 日本神経科学会

 

担当授業科目 【 表示 / 非表示

  • 生理学Ⅰ

    2019年度

担当経験のある授業科目 【 表示 / 非表示

  • 生理学I実習

    慶應義塾, 2017年度, 秋学期, 専門科目, 実習・実験

  • 生理学I

    慶應義塾, 2017年度, 春学期, 専門科目, 講義