We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. 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, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of CREG, 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.

中文翻译：

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在自闭症基因突变和一类新型常见遗传修饰符的交叉点上，稳态可塑性失败

我们确定了一组常见的表型修饰符，它们与五个独立的自闭症基因直向同源物（RIMS1、CHD8、CHD2、WDFY3、ASH1L）相互作用，导致果蝇突触前稳态可塑性（PHP）的常见失败。每个自闭症基因中的杂合无效突变被证明具有正常的基线神经传递和 PHP。但是，PHP 很敏感并且容易出现故障。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突变，这些突变通常与多个 ASD 基因直向同源基因相互作用，导致 PHP 失败。对屏幕中确定的两个表型修饰符 PDPK1 和 PPP2R5D 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；CREG 的意外的、适应不良的上调，一个保守的，神经元表达的应激反应基因和新型 PHP 抑制因子。因此，我们定义了一个新的遗传景观，通过该景观，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。