Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama, Japan.
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama, Japan; Support Unit for Bio-Material Analysis, Research Resources Division, RIKEN Center for Brain Science, Saitama, Japan.
EBioMedicine. 2019 Jul;45:432-446. doi: 10.1016/j.ebiom.2019.05.062. Epub 2019 Jun 26.
Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic.
Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses.
The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with "betaine deficit-oxidative stress pathology". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy.
The present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia. FUND: This study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018-2809 (YK) and RIKEN Epigenetics Presidential Fund (100214-201801063606-340120) (TY).
甜菜碱具有抵抗多种生物应激的作用，其水平在精神分裂症患者中降低。我们旨在检验甜菜碱在精神分裂症病理生理学中的作用，并评估其作为新型精神治疗剂的潜力。
使用 Chdh（甜菜碱合成基因）缺陷小鼠和补充甜菜碱的近交系小鼠，通过代谢组学、行为学、转录组学和 DNA 甲基化分析，评估甜菜碱在精神病理生理学中的作用及其作为新型精神治疗剂的潜力。
Chdh 缺陷小鼠表现出残留的精神行为以及大脑中与精神分裂症相关的分子改变。甜菜碱补充可引起遗传背景依赖性认知表现改善，并抑制甲基苯丙胺（MAP）诱导的行为敏化。此外，甜菜碱还纠正了 MAP 和体外苯环利定（PCP）处理诱导的抗氧化和促炎反应的改变。甜菜碱还对 PCP 诱导的行为异常表现出预防作用。值得注意的是，精神分裂症患者死后大脑中的甜菜碱水平降低，同时存在共存的羰基应激（氧化应激的一种形式），这标志着一部分精神分裂症患者存在“甜菜碱缺乏-氧化应激病理”。我们发现，糖氧酶 1（GLO1）缺陷的诱导多能干细胞（hiPSC）中存在甜菜碱水平降低和羰基应激升高，甜菜碱可减轻羰基应激，这支持了甜菜碱与氧化应激状态之间的因果关系。此外，在精神分裂症患者死后大脑中，鉴定出 CHDH 变体 rs35518479 是 CHDH 表达的顺式表达数量性状基因座（eQTL），这允许基于基因型对精神分裂症患者进行甜菜碱疗效的分层。
本研究揭示了甜菜碱在精神病理生理学中的作用，并强调了甜菜碱在精神分裂症的一部分患者中的潜在益处。
本研究得到了 AMED（日本医疗研究与发展机构）战略研究计划脑科学的支持，资助编号为 JP18dm0107083 和 JP19dm0107083（TY）、JP18dm0107129（MM）、JP18dm0107086（YK）、JP18dm0107107（HY）、JP18dm0107104（AK）和 JP19dm0107119（KH），由文部科学省的创新领域研究计划资助，资助编号为 JP18H05435（TY）、JP18H05433（AH.-T）、JP18H05428（AH.-T 和 TY）和 JP16H06277（HY），以及由日本学术振兴会科学研究资助计划资助，资助编号为 JP17H01574（TY）。此外，本研究还得到了新泻大学脑研究所合作研究项目的支持，资助编号为 2018-2809（YK）和 RIKEN 表观遗传学总统基金（100214-201801063606-340120）（TY）。
