Frasch Martin G, Yoon Byung-Jun, Helbing Dario Lucas, Snir Gal, Antonelli Marta C, Bauer Reinhard
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA.
Center on Human Development and Disability, University of Washington, Seattle, WA 98195, USA.
Biology (Basel). 2023 Jun 26;12(7):914. doi: 10.3390/biology12070914.
Fetal neuroinflammation and prenatal stress (PS) may contribute to lifelong neurological disabilities. Astrocytes and microglia, among the brain's non-neuronal "glia" cell populations, play a pivotal role in neurodevelopment and predisposition to and initiation of disease throughout lifespan. One of the most common neurodevelopmental disorders manifesting between 1-4 years of age is the autism spectrum disorder (ASD). A pathological glial-neuronal interplay is thought to increase the risk for clinical manifestation of ASD in at-risk children, but the mechanisms remain poorly understood, and integrative, multi-scale models are needed. We propose a model that integrates the data across the scales of physiological organization, from genome to phenotype, and provides a foundation to explain the disparate findings on the genomic level. We hypothesize that via gene-environment interactions, fetal neuroinflammation and PS may reprogram glial immunometabolic phenotypes that impact neurodevelopment and neurobehavior. Drawing on genomic data from the recently published series of ovine and rodent glial transcriptome analyses with fetuses exposed to neuroinflammation or PS, we conducted an analysis on the Simons Foundation Autism Research Initiative (SFARI) Gene database. We confirmed 21 gene hits. Using unsupervised statistical network analysis, we then identified six clusters of probable protein-protein interactions mapping onto the immunometabolic and stress response networks and epigenetic memory. These findings support our hypothesis. We discuss the implications for ASD etiology, early detection, and novel therapeutic approaches. We conclude with delineation of the next steps to verify our model on the individual gene level in an assumption-free manner. The proposed model is of interest for the multidisciplinary community of stakeholders engaged in ASD research, the development of novel pharmacological and non-pharmacological treatments, early prevention, and detection as well as for policy makers.
胎儿神经炎症和产前应激（PS）可能导致终身神经残疾。在大脑的非神经元“神经胶质”细胞群体中，星形胶质细胞和小胶质细胞在神经发育以及整个生命周期中疾病的易感性和发病过程中起着关键作用。1至4岁之间最常见的神经发育障碍之一是自闭症谱系障碍（ASD）。病理性神经胶质-神经元相互作用被认为会增加高危儿童出现ASD临床表现的风险，但其机制仍知之甚少，因此需要综合的多尺度模型。我们提出了一个模型，该模型整合了从基因组到表型的生理组织各尺度的数据，并为解释基因组水平上的不同发现提供了基础。我们假设，通过基因-环境相互作用，胎儿神经炎症和PS可能会重新编程影响神经发育和神经行为的神经胶质免疫代谢表型。利用最近发表的一系列绵羊和啮齿动物神经胶质转录组分析的基因组数据，这些分析针对暴露于神经炎症或PS的胎儿，我们对西蒙斯基金会自闭症研究倡议（SFARI）基因数据库进行了分析。我们确认了21个基因命中。然后，我们使用无监督统计网络分析，确定了六个可能的蛋白质-蛋白质相互作用簇，这些簇映射到免疫代谢和应激反应网络以及表观遗传记忆上。这些发现支持了我们的假设。我们讨论了对ASD病因、早期检测和新治疗方法的影响。我们最后描述了以无假设方式在个体基因水平上验证我们模型的下一步措施。所提出的模型对于参与ASD研究、新型药物和非药物治疗开发、早期预防和检测的多学科利益相关者群体以及政策制定者来说是有意义的。
