1. Neuroscience

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

  1. Özgür Genç
  2. Joon-Yong An
  3. Richard D Fetter
  4. Yelena Kulik
  5. Giulia Zunino
  6. Stephan J Sanders
  7. Graeme W Davis  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.55775
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  1. Özgür Genç
  2. Joon-Yong An
  3. Richard D Fetter
  4. Yelena Kulik
  5. Giulia Zunino
  6. Stephan J Sanders
  7. Graeme W Davis
(2020)
Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers
eLife 9:e55775.
https://doi.org/10.7554/eLife.55775
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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

Article and author information

Author details

  1. Özgür Genç

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  2. Joon-Yong An

    Department of Psychiatry, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  3. Richard D Fetter

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  4. Yelena Kulik

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  5. Giulia Zunino

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  6. Stephan J Sanders

    Department of Psychiatry, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  7. 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.
    ORCID icon "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.

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Version history

  1. Received: February 5, 2020
  2. Accepted: June 7, 2020
  3. Accepted Manuscript published: July 1, 2020 (version 1)
  4. Version of Record published: July 31, 2020 (version 2)

Copyright

© 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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  1. Özgür Genç
  2. Joon-Yong An
  3. Richard D Fetter
  4. Yelena Kulik
  5. Giulia Zunino
  6. Stephan J Sanders
  7. Graeme W Davis
(2020)
Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers
eLife 9:e55775.
https://doi.org/10.7554/eLife.55775

Share this article

https://doi.org/10.7554/eLife.55775

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