Institute of Physiology, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany.
Int J Mol Sci. 2021 Jul 6;22(14):7273. doi: 10.3390/ijms22147273.
Mutations in TSC1 or TSC2 genes are linked to alterations in neuronal function which ultimately lead to the development of a complex neurological phenotype. Here we review current research on the effects that reduction in TSC1 or TSC2 can produce on the developing neural network. A crucial feature of the disease pathophysiology appears to be an early deviation from typical neurodevelopment, in the form of structural abnormalities. Epileptic seizures are one of the primary early manifestation of the disease in the CNS, followed by intellectual deficits and autism spectrum disorders (ASD). Research using mouse models suggests that morphological brain alterations might arise from the interaction of different cellular types, and hyperexcitability in the early postnatal period might be transient. Moreover, the increased excitation-to-inhibition ratio might represent a transient compensatory adjustment to stabilize the developing network rather than a primary factor for the development of ASD symptoms. The inhomogeneous results suggest region-specificity as well as an evolving picture of functional alterations along development. Furthermore, ASD symptoms and epilepsy might originate from different but potentially overlapping mechanisms, which can explain recent observations obtained in patients. Potential treatment is determined not only by the type of medicament, but also by the time point of treatment.
TSC1 或 TSC2 基因突变与神经元功能改变有关，最终导致复杂的神经表型的发展。在这里，我们回顾了目前关于 TSC1 或 TSC2 减少对发育中神经网络影响的研究。疾病病理生理学的一个关键特征似乎是早期偏离典型的神经发育，表现为结构异常。癫痫发作是中枢神经系统疾病的主要早期表现之一，其次是智力缺陷和自闭症谱系障碍 (ASD)。使用小鼠模型的研究表明，形态学脑改变可能源于不同细胞类型的相互作用，并且早期产后的过度兴奋可能是短暂的。此外，兴奋性与抑制性的比值增加可能代表一种对发育中网络的稳定的短暂代偿性调整，而不是 ASD 症状发展的主要因素。不均匀的结果表明存在区域特异性以及功能改变随发育而演变的情况。此外，ASD 症状和癫痫可能源自不同但潜在重叠的机制，这可以解释最近在患者中获得的观察结果。潜在的治疗方法不仅取决于药物的类型，还取决于治疗的时间点。
