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Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells

  1. Yuntao Duan
  2. Shih-Hsiu Wang
  3. Juan Song
  4. Yevgeniya Mironova
  5. Guo-li Ming
  6. Alex L Kolodkin
  7. Roman J Giger  Is a corresponding author
  1. University of Michigan School of Medicine, United States
  2. Johns Hopkins University School of Medicine, United States
  3. University of North Carolina, United States
Research Article
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Cite this article as: eLife 2014;3:e04390 doi: 10.7554/eLife.04390

Abstract

Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene, however its function in brain development is unknown. Here we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally-born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A-/- GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co-expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A-/- mutants, PlexinA2-/- mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A-/- mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally- and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders.

Article and author information

Author details

  1. Yuntao Duan

    University of Michigan School of Medicine, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shih-Hsiu Wang

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Juan Song

    University of North Carolina, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yevgeniya Mironova

    University of Michigan School of Medicine, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Guo-li Ming

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alex L Kolodkin

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Roman J Giger

    University of Michigan School of Medicine, Ann Arbor, United States
    For correspondence
    rgiger@umich.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All mice used in this study were housed and cared for in accordance with NIH guidelines, and all research conducted was done with the approval of the University of Michigan Medical School (UCUCA protocols PRO00002466 and PRO00001645) and The Johns Hopkins University (MO14M50 and MO12M381) Committees on Use and Care of Animals. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Freda Miller, The Hospital for Sick Children Research Institute, University of Toronto, Canada

Publication history

  1. Received: August 16, 2014
  2. Accepted: October 13, 2014
  3. Accepted Manuscript published: October 14, 2014 (version 1)
  4. Version of Record published: November 19, 2014 (version 2)

Copyright

© 2014, Duan 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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