School of Pharmacy, University of Bologna, Bologna, Italy.
Islamic Azad University Pharmaceutical Sciences Branch, Tehran, Iran.
Am J Med Genet B Neuropsychiatr Genet. 2024 Dec;195(8):e32986. doi: 10.1002/ajmg.b.32986. Epub 2024 Jun 4.
Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.
自闭症谱系障碍（ASD）是一种复杂的神经行为疾病，受多种细胞和分子机制的影响，这些机制通常与突触发生和突触活性有关。基于兴奋/抑制（E/I）失衡理论，ASD 可能是大脑中兴奋和抑制性突触传递中断的结果。前额叶皮层（PFC）是执行功能的主要调节者，在 ASD 过程中，神经元兴奋和抑制的改变可能会影响到它。涉及 E/I 失衡的分子机制受到表观遗传调控的影响。在 ASD 中，PFC 中组蛋白 H3 和 H4 修饰的富集和扩散发生改变，例如激活相关的 H3K4me2/3、H3K9ac 和 H3K27ac，以及抑制相关的 H3K9me2、H3K27me3 和 H4K20me2，导致调节突触兴奋（ARC、EGR1、mGluR2、mGluR3、GluN2A 和 GluN2B）和突触抑制（BSN、EphA7、SLC6A1）的分子失调。组蛋白修饰是表观遗传调节元件的动态组成部分，对任何生物过程的基因表达模式都有显著影响。与 ASD 相关的兴奋/抑制失衡是基于大脑不同区域（包括 PFC）的兴奋和抑制性突触活性，其最终结果高度受相关基因转录活性的影响。
