Koike-Kumagai Makiko, Fujimoto Manabu, Wataya-Kaneda Mari
Department of Neurocutaneous Medicine, Division of Health Sciences, Graduate School of Medicine, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Department of Dermatology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Pharmacol Biochem Behav. 2024 Dec;245:173875. doi: 10.1016/j.pbb.2024.173875. Epub 2024 Sep 6.
The sex of the patient often affects the prevalence, progression, and severity of many psychiatric disorders. The incidence, progression, and severity of Parkinson's disease and Alzheimer's disease, the most common neurodegenerative diseases, also differ between the sexes. Sex differences in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and anxiety are also observed in tuberous sclerosis complex (TSC). Neuropsychiatric symptoms are one of the most important manifestations of TSC, and the multiple neuropsychiatric symptoms are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). We created TSC model mice (Tsc2 conditional knockout [cKO] mice) that developed epilepsy and TAND. Sex-based differences were observed for hyperactivity and cognitive dysfunctions in Tsc2 cKO mice with TAND, indicating more severe symptoms in female mice than in male mice. TSC is thought to be caused by the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1), and mTORC1 inhibitors improve almost all TSC symptoms. Treatment with sirolimus, an mTORC1 inhibitor, improved TAND in Tsc2 cKO mice. We aimed to elucidate the mechanism underlying sex-based differences in TAND using Tsc2 cKO mice and sirolimus. We found that estradiol (E2) and estrogen receptor (ER)α are involved in sex differences in neuropsychiatric symptoms, and discovered a novel function of sirolimus. We showed that sirolimus ameliorated TAND by modulating brain steroid levels and regulating E2/ERα-dependent transcriptional activation. This indicates sirolimus may be beneficial for the treatment of TAND as well as diseases caused by sex-based differences and steroid levels.
患者的性别常常会影响许多精神疾病的患病率、进展和严重程度。帕金森病和阿尔茨海默病这两种最常见的神经退行性疾病，其发病率、进展和严重程度在性别之间也存在差异。在结节性硬化症（TSC）中，也观察到了自闭症谱系障碍（ASD）、注意力缺陷多动障碍（ADHD）和焦虑症中的性别差异。神经精神症状是TSC最重要的表现之一，多种神经精神症状统称为TSC相关神经精神障碍（TAND）。我们创建了出现癫痫和TAND的TSC模型小鼠（Tsc2条件性敲除[cKO]小鼠）。在患有TAND的Tsc2 cKO小鼠中，观察到了基于性别的多动和认知功能障碍差异，表明雌性小鼠的症状比雄性小鼠更严重。TSC被认为是由雷帕霉素机制靶点复合物1（mTORC1）的过度激活引起的，mTORC1抑制剂几乎可以改善所有TSC症状。用mTORC1抑制剂西罗莫司治疗可改善Tsc2 cKO小鼠的TAND。我们旨在利用Tsc2 cKO小鼠和西罗莫司阐明TAND中基于性别的差异的潜在机制。我们发现雌二醇（E2）和雌激素受体（ER）α参与了神经精神症状的性别差异，并发现了西罗莫司的一种新功能。我们表明西罗莫司通过调节脑类固醇水平和调节E2/ERα依赖性转录激活来改善TAND。这表明西罗莫司可能对治疗TAND以及由性别差异和类固醇水平引起的疾病有益。
