Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers
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.
Sequencing data have been deposited in GEO under accession code GSE153225. Analysis code is available via Github https://github.com/joonan30/Genc2020_RNAseq
Transcriptomics analysis of heterozygous mutant and wild-type flies for presynaptic homeostatic plasticityNCBI Gene Expression Omnibus, GSE153225.
Analysis codeGithub, Genc2020_RNAseq.
Article and author information
National Institute of Neurological Disorders and Stroke (R35-NS097212)
- Graeme W Davis
Simons Foundation (SFARI #401636)
- Graeme W Davis
Simons Foundation (SFARI #402281)
- Stephan J Sanders
National Institute of Mental Health (R01 MH110928)
- Stephan J Sanders
- Joon-Yong An
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Hugo J Bellen, Baylor College of Medicine, United States
- Received: February 5, 2020
- Accepted: June 7, 2020
- Accepted Manuscript published: July 1, 2020 (version 1)
- Version of Record published: July 31, 2020 (version 2)
© 2020, Genç et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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