1. Biochemistry and Chemical Biology
  2. Neuroscience

A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency

  1. Tara L Mastro  Is a corresponding author
  2. Anthony Preza
  3. Shinjini Basu
  4. Sumantra Chattarji
  5. Sally M Till
  6. Peter C Kind
  7. Mary B Kennedy  Is a corresponding author
  1. California Institute of Technology, United States
  2. University of Edinburgh, United Kingdom
  3. National Centre for Biological Sciences, Tata Institute of Fundamental Research, India
https://doi.org/10.7554/eLife.52656
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  1. Tara L Mastro
  2. Anthony Preza
  3. Shinjini Basu
  4. Sumantra Chattarji
  5. Sally M Till
  6. Peter C Kind
  7. Mary B Kennedy
(2020)
A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency
eLife 9:e52656.
https://doi.org/10.7554/eLife.52656
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Abstract

SynGAP is a postsynaptic density (PSD) protein that binds to PDZ domains of the scaffold protein PSD-95. We previously reported that heterozygous deletion of Syngap1 in mice is correlated with increased steady-state levels of other key PSD proteins that bind PSD-95, although the level of PSD-95 remains constant (Walkup et al., 2016). For example, the ratio to PSD-95 of Transmembrane AMPA-Receptor-associated Proteins (TARPs), which mediate binding of AMPA-type glutamate receptors to PSD-95, was increased in young Syngap1+/- mice. Here we show that only females and not males show a highly significant correlation between an increase in TARP and a decrease in synGAP in the PSDs of Syngap1+/- rodents. The data reveal a sex difference in the adaptation of the PSD scaffold to synGAP haploinsufficiency.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Tara L Mastro

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    tmastro@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.

  2. Anthony Preza

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Shinjini Basu

    Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Sumantra Chattarji

    National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9962-3635

  5. Sally M Till

    Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Peter C Kind

    Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4256-9639

  7. Mary B Kennedy

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    kennedym@its.caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1369-0525

Funding

National Institute of Mental Health (MH15456)

  • Tara L Mastro
  • Anthony Preza
  • Mary B Kennedy

Allen and Lenabelle Davis Foundation (Professorship)

  • Mary B Kennedy

National Science Foundation (Postdoctoral Fellowship)

  • Tara L Mastro

Department of Biotechnology , Ministry of Science and Technology

  • Sumantra Chattarji
  • Peter C Kind

Simons Foundation (Grant 529085)

  • Peter C Kind

Patrick Wild Centre (Patrick Wild Centre)

  • Sally M Till
  • Peter C Kind

Medical Research Council (MR/P006213/1)

  • Sally M Till
  • Peter C Kind

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (1034-18) of California Institute of Technology.

Copyright

© 2020, Mastro 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. Tara L Mastro
  2. Anthony Preza
  3. Shinjini Basu
  4. Sumantra Chattarji
  5. Sally M Till
  6. Peter C Kind
  7. Mary B Kennedy
(2020)
A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency
eLife 9:e52656.
https://doi.org/10.7554/eLife.52656

Share this article

https://doi.org/10.7554/eLife.52656

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Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience

    A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

    Ward G Walkup IV, Tara L Mastro ... Mary B Kennedy
    Research Article Updated

    SynGAP is a Ras/Rap GTPase-activating protein (GAP) that is a major constituent of postsynaptic densities (PSDs) from mammalian forebrain. Its α1 isoform binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95, the principal PSD scaffold, and can occupy as many as 15% of these PDZ domains. We present evidence that synGAP-α1 regulates the composition of the PSD by restricting binding to the PDZ domains of PSD-95. We show that phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Polo-like kinase-2 (PLK2) decreases its affinity for the PDZ domains by several fold, which would free PDZ domains for occupancy by other proteins. Finally, we show that three critical postsynaptic signaling proteins that bind to the PDZ domains of PSD-95 are present in higher concentration in PSDs isolated from mice with a heterozygous deletion of synGAP.