Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers.

Abstract

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