Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United States
Joon-Yong An
Department of Psychiatry UCSF Weill Institute for Neurosciences University of California, San Francisco, San Francisco, United States; School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea
Richard D Fetter
Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United States
Yelena Kulik
Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United States
Giulia Zunino
Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United States
Stephan J Sanders
Department of Psychiatry UCSF Weill Institute for Neurosciences University of California, San Francisco, San Francisco, United States
Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United States
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.
