シンポジウム (Symposia)

神経化学・生物精神の共催シンポジウム「気分障害におけるグリアの異常」 Joint Symposium of the Japanese Society of Neurochemistry and Japanese Society of Biological Sciences
S3-2-1-1 うつ病の分子病態におけるグリア細胞の役割 Involvement of glial functions in a cause of depression ○小泉修一¹ ○Schuichi Koizumi¹ 山梨大・院・医工・医学学域・薬理¹ Dept. Neuropharmacol, Grad. Sch. Med., Univ. Yamanashi¹ It is generally believed that selective serotonin reuptake inhibitors (SSRIs) act on neurons, inhibit uptake of serotonin, and show their anti-depressant effects. Recent accumulating evidence show that astrocytes control a big variety of neuronal activities, including synaptic transmission, and therefore their contributions to brain functions are not negligible. Thus, astrocytes being exposed to psychotropic drugs could contribute to their therapeutic effects. Brain-derived neurotropic factor (BDNF) has received attention as an important molecule to be related in depression. BDNF participates in neuronal survival, outgrowth, remodeling and possibly neurogenesis, and its decrease or deficiency is involved in cause of depression. Although astrocytes do not express BDNF in general, here we show that astrocytes respond to the SSRI fluoxetine, and upregulate BDNF. When treated with fluoxetine, astrocytes upregulated mRNAs and proteins for BDNF in a concentration-dependent fashion. The fluoxetine-evoked increase in BDNF was independent of serotonin but was dependent on extracellular ATP and its metabolite adenosine. When stimulated with fluoxetine, astrocytes released ATP, a typical gliotransmitter, by a mechanism of exocytosis. Pharmacological and molecular biochemical analysis revealed that P2Y11 and adenosine A2b receptors were responsible for the BDNF production. As for intracellular signaling cascades, we found that activation of both P2Y11 and A2b receptors resulted in PKA-mediated phosphorylation of CREB, thereby leading to BDNF transcription. Chronic administration of fluoxetine in mice also increased BDNF expression in astrocytes. These all findings suggest that astrocytes could be a therapeutic target for anti-depressants and would be involved in pathogenesis of depression.	S3-2-1-2 抗うつ作用から見たアストロサイトの役割 Role of astrocytes in antidepressant action ○竹林実¹ ○Minoru Takebayashi¹ 国立病院機構呉医療センター・中国がんセンター　精神科・臨床研究部¹ Dept Psychiatry/Institute for Clinical Res, NHO Kure Medical Center, Kure, Japan¹ Astrocytes are regarded as the most abundant cell type in the brain and are known for their housekeeping functions such as being a reservoir of neurotrophic factors. Recent developments suggest that astrocytes control adult hippocampal neurogenesis and are dynamic regulators of synaptogenesis and synaptic strength and stability. In the rat cell culture system, we demonstrated that treatment with tricyclic antidepressants significantly increases the expression of fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor, vascular endothelial growth factor, and glial cell line-derived neurotrophic factor mRNA in cortical and hippocampal astrocytes, but not in neurons. All four factors have been implicated in the antidepressant effect. Antidepressant-induced production in FGF-2 was mediated through a monoamine-independent pathway. On the other hand, in adult rat dentate gyrus (DG)-derived neural precursor cells (ADP), which are considered to be involved in neurogenesis and therapeutic effects in mood disorders, antidepressants have no direct effects on ADP proliferation. However, the conditioned medium (CM) from astrocytes, treated with antidepressants, increases ADP proliferation. As a result of further investigation, we found that antidepressant-induced FGF-2 secretion in astrocytes was the most important factor of CM to increase ADP proliferation. Therefore, astrocytes may mediate the antidepressants-induced proliferation of neural precursor cells in adult DG (neurogenesis) through FGF-2 secretion. Taken together, astrocytes, which have been reported to less prevalent in several areas in mood disorders, could contribute to the pathophysiology of mood disorders, and the monoamine-independent novel targets of antidepressants in astrocytes might contribute to the development of more efficient treatments.
S3-2-1-3 ミクログリア仮説に基づく気分障害の病態解明に向けたアプローチ ○加藤隆弘¹ ○Takahiro Kato¹ 九州大学医学研究院¹ Kyushu University¹	S3-2-1-4 ストレスを感知するmicrogliaがうつ病治療の新たなターゲットとなるか Microglia senses psychological stress: Target for novel antidepressant agents ○岩田正明¹ ○Masaaki Iwata¹ 鳥取大学　医学部　精神行動医学分野¹ Tottori University School of Medicine, Division of Neuropsychiatry, Tottori¹ Major depressive disorder (MDD) patients express volume loss in cortical and limbic brain regions, due to the reduction of synaptic density and the decremental numbers of neurons. Pre-clinical studies have demonstrated that stress causes morphological alterations such as suppressed neurogenesis. Protection against this neuronal damage is an important strategy for treating MDD, though the mechanisms by which stress causes this neuronal damage is not well known. Serum levels of pro-inflammatory cytokines such as interleukin 1β (IL-1β) are elevated in MDD patients, while chronic inflammatory diseases such as diabetes show high comorbidity with depression. Taken together, this suggests that inflammation is involved in the pathology of depression. We have previously shown that acute stress increases IL-1β in the hippocampus (HIP), and IL-1β suppresses neurogenesis and shows depressive-like behavior in rodents. The synthesis and release of IL-1β are regulated by P2X7 receptor in microglia, the primary source of this cytokine in brain. In support of this, ATP is rapidly up-regulated by stress in HIP. To further evaluate the role of the ATP-P2X7-IL-1β signaling, we examined the effect of A804598, a selective P2X7 receptor antagonist. We found that the inhibition of hippocampal neurogenesis caused by acute stress was completely blocked by A804598. Moreover, depressive-like behavior in the chronic stress model was reversed by chronic administration of A804598. Downstream of the P2X7 receptor is the NLRP3 inflammasome, a large protein complex that controls activation of IL-1β. Thus, we hypothesize that stress increases ATP release, which is sensed by microglia, activating NLRP3 inflammasome and increasing the release of IL-1β, causing depression. Because of the role of NLRP3 inflammasome as a broad range sensor of danger substances, it may be a promising target for treatment of depression.

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