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Spatiotemporal regulation of glutamate distribution by transporters (EAATs/VGLUTs) and implications in neuropsychiatric disorders

開催日 2014/9/13
時間 9:00 - 11:00
会場 Room E(301)
Chairperson(s) 田中 光一 / Kohichi Tanaka (東京医科歯科大学難治疾患研究所分子神経科学分野 / Medical Research Institute & CBIR, Tokyo Medical & Dental University, Japan)
木下 専 / Makoto Kinoshita (名古屋大学大学院理学研究科生命理学専攻 / Department of Molecular Biology, Nagoya University Graduate School of Science, Japan)

Role of the glutamate transporter in depression-like behaviors

  • S3-E-1-1
  • 相澤 秀紀 / Hidenori Aizawa:1 崔 万鵬 / Wanpeng Cui:1 水上 浩明 / Hiroaki Mizukami:2 柳澤 美智子 / Michiko Yanagisawa:1 相田 知海 / Tomomi Aida:1 野村 政壽 / Masatoshi Nomura:3 礒村 宜和 / Yoshikazu Isomura:4 高柳 涼一 / Ryoichi Takayanagi:3 小澤 敬也 / Keiya Ozawa:2 田中 光一 / Kohichi Tanaka:1,5,6 
  • 1:医科歯科大、難治研、分子神経 / Lab Mol Neurosci, Med Res Inst, Tokyo Med & Dent Univ, Japan 2:自治医大、分子病態治療センター、遺伝子治療 / Dept Med Bioreg Sci, Grad Sch Med Sci, Kyushu Univ, Japan 3:九州医、病態制御内科学分野 / Dept Med Bioreg Sci, Grad Sch Med Sci, Kyushu Univ, Japan 4:玉川大、脳研 / Brain Sci Inst, Tamagawa Univ., Japan 5:日本学術振興会 / CREST, JST, Japan 6:医科歯科大 、脳統合機能研究センター / Cent Brain Int Res, Tokyo Med & Dent Univ, Japan 

Growing evidence reported reduction of glutamate transporter EAAT2 (GLT-1 in rodents) expression in patients with major depression and in rat models of depression, suggesting that enhanced excitatory neurotransmission via reduced glial glutamate transport activity underlies depression. However, the neural pathway through which the defective GLT-1 affects the depressive behavior remains unclear. The lateral habenula (LHb) regulates the activity of monoaminergic neurons in the brain stem and has recently attracted a surge of interest in psychiatry because studies have reported the pathological activation of the habenula in patients with major depression and in animal models. To address the hypothesis that defects of GLT-1 in LHb cause the depression-like behaviors, we generated the mice with inhibition of the glial glutamate transporter GLT-1 in the LHb. The habenula-specific inhibition of GLT-1 increased the firing rate of LHb neurons and suppressed c-Fos expression in the monoaminergic neurons in the brain stem. Mice with reduced GLT-1 activity in the habenula exhibited a depressive phenotype in the tail suspension and novelty-suppressed feeding tests. These animals also displayed increased susceptibility to chronic stress, showing more frequent avoidant behavior without affecting locomotor activity in the open-field test. Intriguingly, the mice showed disinhibition of rapid eye movement sleep, which is a characteristic sleep pattern in patients with depression. These results provide the first evidence that disrupting glutamate clearance function in the habenular astrocytes increases neuronal excitability and depressive-like phenotypes in behaviors and sleep.

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