Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United States.
Department of Psychiatry UCSF Weill Institute for Neurosciences University of California, San Francisco, San Francisco, United States.
Elife. 2020 Jul 1;9:e55775. doi: 10.7554/eLife.55775.
We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (, , , , ) causing a common failure of presynaptic homeostatic plasticity (PHP) in . Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, and are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of , a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.
我们鉴定出了一组常见的表型修饰因子，它们与五个独立的自闭症基因直系同源物（、、、、）相互作用，导致在中共同出现突触前自身稳态可塑性（PHP）的失败。每个自闭症基因的杂合性缺失突变被证明具有正常的基础神经传递和 PHP。然而，PHP 变得敏感并容易出现故障。随后的基于电生理学的遗传筛选确定了第一个已知的杂合性突变，这些突变通常与多个 ASD 基因直系同源物发生遗传相互作用，导致 PHP 失败。在筛选中鉴定出的两个表型修饰因子和进行了表征。最后，转录组学、超微结构和电生理学分析定义了 PHP 失败的一种机制；一种出乎意料的、适应不良的上调，这是一种保守的、神经元表达的、应激反应基因，也是 PHP 的一种新型抑制剂。因此，我们定义了一个新的遗传景观，通过这个景观，不同的、不相关的自闭症风险基因可能会聚在一起，共同影响突触传递的稳健性。
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