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

Abstract
Data availability
Article and author information
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Abstract

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.

Data availability

Sequencing data have been deposited in GEO under accession code GSE153225. Analysis code is available via Github https://github.com/joonan30/Genc2020_RNAseq

The following data sets were generated

1. Genç O
2. An J-Y
3. Fetter RD
4. Kulik Y
5. Zunino G
6. Sanders SJ
7. Davis GW
(2020) Transcriptomics analysis of heterozygous mutant and wild-type flies for presynaptic homeostatic plasticity
NCBI Gene Expression Omnibus, GSE153225.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153225
1. Genç O
2. An J-Y
3. Fetter RD
4. Kulik Y
5. Zunino G
6. Sanders SJ
7. Davis GW
(2020) Analysis code
Github, Genc2020_RNAseq.

https://github.com/joonan30/Genc2020_RNAseq

Article and author information

Author details

Özgür Genç

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Joon-Yong An

Department of Psychiatry, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Richard D Fetter

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Yelena Kulik

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Giulia Zunino

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Stephan J Sanders

Department of Psychiatry, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Graeme W Davis

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

For correspondence
graeme.davis@ucsf.edu

Competing interests
Graeme W Davis, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0003-1355-8401

Funding

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

NRF (2017M3C7A1026959)

Joon-Yong An

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

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.