Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Autism Center of Excellence, University of California, San Diego, San Diego, CA 92037, USA.
Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Autism Center of Excellence, University of California, San Diego, San Diego, CA 92037, USA; Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
Trends Neurosci. 2020 May;43(5):326-342. doi: 10.1016/j.tins.2020.03.005. Epub 2020 Apr 15.
Autism spectrum disorder (ASD) is a largely heritable, multistage prenatal disorder that impacts a child's ability to perceive and react to social information. Most ASD risk genes are expressed prenatally in many ASD-relevant brain regions and fall into two categories: broadly expressed regulatory genes that are expressed in the brain and other organs, and brain-specific genes. In trimesters one to three (Epoch-1), one set of broadly expressed (the majority) and brain-specific risk genes disrupts cell proliferation, neurogenesis, migration, and cell fate, while in trimester three and early postnatally (Epoch-2) another set (the majority being brain specific) disrupts neurite outgrowth, synaptogenesis, and the 'wiring' of the cortex. A proposed model is that upstream, highly interconnected regulatory ASD gene mutations disrupt transcriptional programs or signaling pathways resulting in dysregulation of downstream processes such as proliferation, neurogenesis, synaptogenesis, and neural activity. Dysregulation of signaling pathways is correlated with ASD social symptom severity. Since the majority of ASD risk genes are broadly expressed, many ASD individuals may benefit by being treated as having a broader medical disorder. An important future direction is the noninvasive study of ASD cell biology.
自闭症谱系障碍（ASD）是一种主要具有遗传性的多阶段产前障碍，会影响儿童感知和对社交信息做出反应的能力。大多数 ASD 风险基因在许多与 ASD 相关的大脑区域中都在产前表达，并分为两类：广泛表达的调节基因，在大脑和其他器官中表达，以及大脑特异性基因。在第一到第三个三个月（Epoch-1），一组广泛表达（大多数）和大脑特异性风险基因会破坏细胞增殖、神经发生、迁移和细胞命运，而在第三个三个月和出生后早期（Epoch-2），另一组（大多数是大脑特异性的）会破坏神经突生长、突触发生和皮质的“布线”。一个提出的模型是，上游高度相互关联的调节 ASD 基因突变会破坏转录程序或信号通路，导致下游过程（如增殖、神经发生、突触发生和神经活动）失调。信号通路的失调与 ASD 的社交症状严重程度相关。由于大多数 ASD 风险基因都具有广泛的表达，许多 ASD 个体可能会受益于被视为患有更广泛的疾病。一个重要的未来方向是对 ASD 细胞生物学进行非侵入性研究。
