1. Neuroscience
Download icon

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
Research Article
  • Cited 2
  • Views 1,794
  • Annotations
Cite this article as: eLife 2020;9:e55775 doi: 10.7554/eLife.55775

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

Publication 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.

Metrics

  • 1,794
    Page views
  • 290
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Neuroscience
    Rene Solano Fonseca et al.
    Research Article Updated

    Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Lloyd Davis et al.
    Tools and Resources Updated

    Synthetic strategies for optically controlling gene expression may enable the precise spatiotemporal control of genes in any combination of cells that cannot be targeted with specific promoters. We develop an improved genetic code expansion system in Caenorhabditis elegans and use it to create a photoactivatable Cre recombinase. We laser-activate Cre in single neurons within a bilaterally symmetric pair to selectively switch on expression of a loxP-controlled optogenetic channel in the targeted neuron. We use the system to dissect, in freely moving animals, the individual contributions of the mechanosensory neurons PLML/PLMR to the C. elegans touch response circuit, revealing distinct and synergistic roles for these neurons. We thus demonstrate how genetic code expansion and optical targeting can be combined to break the symmetry of neuron pairs and dissect behavioural outputs of individual neurons that cannot be genetically targeted.