Tuberous sclerosis complex (TSC) is a dominant autosomal genetic disorder caused by loss-of-function mutations in TSC1 and TSC2, which lead to constitutive activation of the mammalian target of rapamycin C1 (mTORC1) with its decoupling from regulatory inputs. Because mTORC1 integrates an array of molecular signals controlling protein synthesis and energy metabolism, its unrestrained activation inflates cell growth and division, resulting in the development of benign tumors in the brain and other organs. In humans, brain malformations typically manifest through a range of neuropsychiatric symptoms, among which mental retardation, intellectual disabilities with signs of autism, and refractory seizures, which are the most prominent. TSC in the rat brain presents the first-rate approximation of cellular and molecular pathology of the human brain, showing many instructive characteristics. Nevertheless, the developmental profile and distribution of lesions in the rat brain, with neurophysiological and behavioral manifestation, deviate considerably from humans, raising numerous research and translational questions. In this study, we revisit brain TSC in human and Eker rats to relate their histopathological, electrophysiological, and neurobehavioral characteristics. We discuss shared and distinct aspects of the pathology and consider factors contributing to phenotypic discrepancies. Given the shared genetic cause and molecular pathology, phenotypic deviations suggest an incomplete understanding of the disease. Narrowing the knowledge gap in the future should not only improve the characterization of the TSC rat model but also explain considerable variability in the clinical manifestation of the disease in humans.

结节性硬化症 (TSC) 是一种显性常染色体遗传性疾病，由TSC1和TSC2的功能丧失突变引起，导致哺乳动物雷帕霉素 C1 靶点 (mTORC1) 的组成性激活，并与调节输入脱钩。由于mTORC1整合了一系列控制蛋白质合成和能量代谢的分子信号，其不受限制的激活会促进细胞生长和分裂，导致大脑和其他器官良性肿瘤的发展。在人类中，大脑畸形通常表现为一系列神经精神症状，其中最突出的是智力低下、伴有自闭症症状的智力障碍和难治性癫痫发作。大鼠大脑中的 TSC 呈现出人脑细胞和分子病理学的一流近似结果，显示出许多有启发性的特征。然而，大鼠大脑中病变的发育概况和分布，以及神经生理学和行为表现，与人类有很大差异，引发了许多研究和转化问题。在这项研究中，我们重新研究了人类和 Eker 大鼠的脑 TSC，以了解它们的组织病理学、电生理学和神经行为特征。我们讨论病理学的共同和独特方面，并考虑导致表型差异的因素。鉴于共同的遗传原因和分子病理学，表型偏差表明对该疾病的了解不完全。未来缩小知识差距不仅可以改善 TSC 大鼠模型的特征，还可以解释人类疾病临床表现的相当大的变异性。