一般口演（Oral）

Oral Antidepressants & Stress 一般口演抗うつ薬・ストレス

7月27日（土）16:30～16:45　第8会場（朱鷺メッセ　3F　303+304） 3O-08e1-1 Eukaryotic elongation factor 2 kinase function in rapid antidepressant action Kanzo Suzuki（Suzuki Kanzo），Ege T Kavalali（Kavalali Ege），Lisa M Monteggia（Monteggia Lisa M） Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA Major depressive disorder is one of the most common mental illnesses. Traditional antidepressants, such as monoamine-reuptake inhibitors, are commonly prescribed to patients with depression but typically take several weeks to exert a clinical effect. There has been a major unmet need in the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data have demonstrated rapid and sustained antidepressant effects of ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist. We previously showed that ketamine and other NMDAR antagonists produce rapid antidepressant-like effects in mouse models. In elucidating the intracellular signaling pathway, we demonstrated that ketamine through block of NMDARs at rest, deactivates eukaryotic elongation factor 2 kinase (eEF2K), which dephosphorylates eukaryotic elongation factor 2 (eEF2), resulting in a subsequent desuppression protein translation including brain-derived neurotrophic factor (BDNF). This signaling pathway then potentiates synaptic AMPAR responses in the hippocampus via insertion of GluA1 and GluA2 subunits. Importantly, administration of eEF2K inhibitors was sufficient to trigger rapid antidepressant action independent of blocking NMDAR and deletion of eEF2K occluded the antidepressant effects of ketamine. While eEF2K is necessary for the rapid antidepressant effects of ketamine, there is little known regarding the role of eEF2K in synaptic plasticity and transmission that could be ultimately important for the therapeutic response. We initially examined eEF2 phosphorylation in hippocampal neurons to understand where eEF2K is localized. We observed high levels of phosphorylated eEF2 in dendrites and spines suggesting that eEF2K functions at postsynaptic sites. We performed whole cell voltage patch clamp electrophysiology experiments to understand the impact of eEF2K inhibition on synaptic function. Data will be presented showing eEF2K plays a role in synaptic efficacy which may provide critical insight into the molecular mechanisms important for rapid antidepressant action.		7月27日（土）16:45～17:00　第8会場（朱鷺メッセ　3F　303+304） 3O-08e1-2 前頭前皮質ミクログリアの自然免疫受容体は反復ストレスによる情動変容に重要である Shiho Kitaoka（北岡志保）¹，Xiang Nie（聶翔）¹，Kohei Tanaka（田中昂平）²，Atsubumi Ogawa（小川惇史）²，Yuki Imoto（井本有基）³，Eri Segi-Nishida（瀬木-西田恵里）⁴，Shuh Narumiya（成宮周）²，Tomoyuki Furuyashiki（古屋敷智之）¹ ¹神戸大院医薬理学分野 ²京都大院医メディカルイノベーションセンター ³京都大院薬生体情報制御 ⁴東京理科大基礎工生物工学 Repeated environmental stress often induces emotional and cognitive disturbances, and can be a risk factor for various psychiatric disorders. To reveal the mechanisms underlying neural and behavioral consequences of repeated environmental stress, repeated stress models in rodents have been employed. Repeated social defeat stress is one of these animal models, and induces social avoidance and elevated anxiety. We previously reported that repeated social defeat stress induces microglial activation. However, the mechanism and the behavioral involvement of this microglial activation remain elusive. Using transcriptome analysis, we found that repeated social defeat stress increased the expression of S100A8 and S100A9, putative ligands for Toll-like receptor (TLR) 2 and 4, in the medial prefrontal cortex. Although mice deficient in either TLR2 or TLR4 showed social avoidance and elevated anxiety after repeated social defeat stress as wild-type mice, simultaneous deficiency of TLR2 and TLR4 abolished these behavioral changes. Repeated social defeat stress activated prefrontal microglia in a TLR2/4 dependent manner, whereas microglia in the nucleus accumbens were not activated. Furthermore, knockdown of TLR2/4 specifically in prefrontal microglia suppressed social avoidance-induced repeated social defeat stress. These results show that repeated social defeat stress induces social avoidance through prefrontal microglial TLR2/4. Whereas environmental stress also alters functions of peripheral organs besides mental functions, whether the interaction exists between the stress-induced changes in the brain and peripheral organs remains elusive. We have recently found that repeated social defeat stress induced mobilization and activation of bone marrow cells, some of which infiltrated to distinct brain regions. We are currently investigating the relationship between the stress-induced microglial activation and monocyte infiltration as well as their behavioral significance.

7月27日（土）17:00～17:15　第8会場（朱鷺メッセ　3F　303+304） 3O-08e1-3 AMPA受容体を標的とした新規抗うつ薬の開発 Tomoyuki Miyazaki（宮? 智之），Nakajima Waki（中島和希），Tetsu Arisawa（有澤哲），Takahashi Takuya（高橋琢哉）横浜市立大学医学部生理学 Depression is the major mental disorder characterized by the decrease of motivation, interest and activity and over one million patients are suffering from this disease. It was also reported that the number of patients showing resistance toward anti-depressant, i.g. SSRI and SNRI, got increase nowadays. We have already known that molecular mechanism underlying depression is heterogeneous so that it is hard to estimate the efficacy of anti-depressant depends without molecular rationale. Postmortem human brain analysis indicated that the number of AMPA receptors (AMPARs), major molecule controlling synaptic functions, varied among depression patients compared to healthy subjects and these results were not consistent. To clarify the dynamics of AMPARs in depression patients, we developed the PET (positron emission tomography) imaging drug to measure the density of AMPARs in depression patients. This result showed that depression patient decreased AMPARs expression broadly throughout the brain. This fact motivated us to develop novel AMPARs potentiator in order to cure the depression. To find the compound showing high affinity to AMPARs and high BBB penetratability, we modified the compound A, previously known to bind specifically to and activate AMPARs, and finally succeeded in synthesizing the seed compound B, showing higher BBB penetratability compared with compound A. This compound B could exert the anti-depressant effect quickly and sustained for a week after withdrawal from repetitive one-week administration. Furthermore, this anti-depressant effect was significantly stronger that another AMPARs potentiators already under development in clinical trials.		7月27日（土）17:15～17:30　第8会場（朱鷺メッセ　3F　303+304） 3O-08e1-4 ROMK(Kir1.1) 遮断薬tertiapinの抗うつ、不安惹起作用 Masayoshi Okada（岡田誠剛）¹，Ikkou kozaki（小﨑一功）²，Hiroyuki Honda（本多裕之）^2,3 ¹倉敷芸科大 ²名古屋大院工生命分子工学 ³名古屋大学予防早期医療創成センター Renal outer medullary K+ channel, ROMK1 (Kir1.1, KCNJ1) is highly expressed in the kidney, and also in the brain. But its role in the central nervous system remains unknown. It is reported that the expression of the channel was 2.5-fold increased in the brains of patients with depression, suggesting an involvement in mental diseases. In addition, some ROMK blockers are now tried to be developed as an antihypertensive drug, and therefore it is necessary to reveal the central effect of ROMK blockade. Tertiapin is a Europian honey bee venom peptide and is reported to selectively block the ROMK channel. Here, we have chemically synthesized a series of mutated tertiapin peptides and examined the blocking activity to ROMK and strongly inwardly rectifying K+ (Kir2.1) channels. The wild type and a mutant, tertiapin-RQ, equally blocked the ROMK channel but not Kir2.1. The examination of the blocking activities of the series of mutated peptides revealed the essential amino acids for the channel blockade, especially four cysteine residues. We next examined the central effect of tertiapin-RQ on mouse depression- and anxiety-like behaviors. Intracerebroventricular injection of tertiapin-RQ showed an antidepressive effect in tail-suspension and forced swim tests. Interestingly, the injection of tertiapin enhanced the anxiety-like behavior in the elevated plus maze and open-field tests, without affecting motor activity in the wheel running. Our results indicate the role of the ROMK in the central nervous system and the advantage and disadvantage as a future drug target.