Vulnerability of social defeats in the overexpressed striatal SHATI/NAT8L in mice

[Speaker] Hajime Miyanishi:1
[Co-author] Kyosuke Uno:1, Toh Miyazaki:1, Kengo Sodeyama:1, Toshiyuki Fuziwara:1, Shin-Ichi Muramatsu:2,3, Yoshiaki Miyamoto:1, Atsumi Nitta:1
1:Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan, 2:Division of Neurology, Jichi Medical University, Shimotsuke, Japan, 3:Center for Gene & Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

[Background] The number of patients that have depressive disorder is increasing. However, the mechanism of depression onsets has not been completely revealed. In such situation, we are mention to SHATI/NAT8L. SHAT/NAT8L is a related protein as psychiatric disorder, and synthesize N-acetyl-aspartate (NAA). NAA is converted to N-acetyl-aspartyl-glutamate (NAAG), an agonist of mGluR3, by condensation with glutamate. We reported that SHATI/NAT8L-overexpressed mice in the striatum showed the prolonged immobility time in the forced swimming test and tail suspension test. Here, we revealed the involvement of SHATI/NAT8L in the vulnerability of social defeats stress by using depression model mice that was exposed to social defeat stress.
[Methods] We exposed repeated social stress to C57BL/6J mice, and confirmed the expression of Shati/Nat8l mRNA in the brain. we generated the SHATI/NAT8L-overexpressed mice by injecting an adeno-associated virus into the dorsal striatum, followed by that mice were exposed the subthreshold micro social defeat stress. Then we performed the social interaction and sucrose preference test. Next, we administrated the selective serotonin reuptake inhibitor fluvoxamine (10 mg/kg i.p.) and the selective mGluR3 antagonist LY341495 (0.03 mg/kg i.p.). we also tried the intracerebral administration of 50uM fluvoxamine (0.5 ul/side) into the striatum. Then we investigated the social interaction.
[results] We found the increase of Shati/Nat8l mRNA expression only in the striatum of mice which were exposed repeated social stress. Only the SHATI/NAT8L-overexpressed mice showed the impairment of social interaction and sucrose preference after the subthreshold micro social defeat stress. These depression-like behaviors were restored by fluvoxamine and LY341495 injection prior these tests. Furthermore, we confirmed the effect of fluvoxamine in the striatum specifically because the intracerebral administration of fluvoxamine also restored.
[conclusions] Taken together, SHATI/NAT8L in the striatum has an important role in the vulnerability of social stress which is related to depression onsets by regulating serotonergic neuronal system. No one report the relationship the function of the striatum and depression like-behavior. Our study suggested the new pathways induce depression like-behaviors, and SHATI/NAT8L in the striatum might be a new target for medical tools for depression.

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