Sex steroids synthesized in the hippocampus as novel neurotn phic factors acutely improving learning and memory efficacy

海马体合成的性类固醇作为新型神经营养因子可显着提高学习和记忆功效

• 批准号: 14380311
• 负责人: KAWATO Suguru
• 金额: $ 9.6万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14380311/
• 关键词: neurosteroid; estradiol; hippocampus; learning and memory; long-term potentiation; estrogen receptor; cytochrome P450; synapse; 記憶学習; 神経成長; シラプス; スパイン; 長期抑圧; 膜上エストロジェン受容体; 電気生理

In the present study, the synthesis of sex steroids, including dehydroepiandrosterone (DHEA), testosterone and 17β-estradiol, has been demonstrated in the adult rat hippocampus by metabolite analysis. The main path for the conversion from DHEA to testosterone in the hippocampus was shown to be 'DHEA→androstenediol→testosterone', which was different from the case in testis (DHEA→androstenedione→testosterone). With immunoelectron microscopy, the localization of essential enzymes for estrogen synthesis, cytochromes P45O17α and P450 aromatase, was demonstrated on membranous structures within spines of principal-neurons at hippocampal CA1 region. The localization of estrogen receptor a in the same structure was also demonstrated. Taken together, it seems to be plausible that estradiol plays a neuromodulative effect in the spine in which it was synthesized or in the spines located in adjacent places via membrane estrogen receptor α.Furthermore, 2-hour treatment of hippocampal slices with estradiol was observed to induce the growth of spine length and the increase of the spine density in CA1 region. Estradiol might exert its effect on neuronal signal transmission via this neurogrowth factor-like action.

在本研究中，性类固醇，包括脱氢表雄酮（DHEA），睾酮和17β-雌二醇的合成，已被证明在成年大鼠海马的代谢物分析。海马中DHEA向睾酮转化的主要途径是DHEA→雄烯二酮→睾酮，而睾丸中DHEA→雄烯二酮→睾酮的转化途径不同。用免疫电镜技术，在海马CA_1区主要神经元棘内的膜结构上，发现了雌激素合成所必需的酶细胞色素P45 O_（17 α）和P450芳香化酶的定位。雌激素受体α在同一结构中的定位也得到了证实。雌二醇可能通过膜雌激素受体α（ER α）在其合成的脊髓或相邻的脊髓中发挥神经调节作用。此外，雌二醇处理海马脑片2 h可引起海马CA 1区脊髓长度增加和密度增加。Escherichia coli可能通过这种神经生长因子样作用对神经元信号传递产生影响。

项目成果

川戸佳: "ステロイドの常識が変わる:第4世代の脳の情報伝達物質ニューロステロイド:海馬が性に関係なく男性・女性ホルモンを合成する"生化学. 75. 1530-1535 (2003)

Yoshi Kawato：“关于类固醇的常识正在改变：神经类固醇是第四代大脑信息传递者：海马体合成男性和女性激素，无论性别”生物化学 75. 1530-1535 (2003)。

Kawato S et al.: "Endocrine disrupters as disrupters of brain function : a neurosteroid view-point."Environ Sci. vol11. 1-14 (2004)

Kawato S 等人：“内分泌干扰物作为大脑功能的干扰物：神经类固醇的观点。”环境科学。

川戸 佳: "記憶学習機能の動的解析手法と求められる技術:脳ニューロステロイドを中心に"バイオサイエンスとインダストリー. 60. 404-407 (2002)

Yoshi Kawato：“记忆学习功能的动态分析方法和所需技术：关注脑神经类固醇”《生物科学与工业》60. 404-407 (2002)。

Shibuya K et al.: "Hippocampal cytochrome P450s synthesize brain neurosteroids which are paracrine neuromodulators of synaptic signal transduction."Biochim Biophys Acta. 1619. 301-316 (2003)

Shibuya K 等人：“海马细胞色素 P450 合成脑神经类固醇，它们是突触信号转导的旁分泌神经调节剂。”Biochim Biophys Acta。

川戸佳, 向井秀夫: "ニューロステロイドによる海馬神経伝達のモジュレーション"医学のあゆみ. 202. 1049-1052 (2002)

Yoshi Kawato、Hideo Mukai：“神经类固醇对海马神经传递的调节”医学史 202. 1049-1052 (2002)。