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

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.

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.

Metrics

  • 4,118
    views
  • 615
    downloads
  • 96
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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
(2014)
Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells
eLife 3:e04390.
https://doi.org/10.7554/eLife.04390

Share this article

https://doi.org/10.7554/eLife.04390

Further reading

    1. Neuroscience
    Chad Heer, Mark Sheffield
    Research Article

    Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently, it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized two-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals’ running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal’s transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, with reward information in VTA inputs and novelty and kinematic information in LC inputs, likely contributing to differential modulation of hippocampal activity during behavior and learning.

    1. Computational and Systems Biology
    2. Neuroscience
    Sebastian Quiroz Monnens, Casper Peters ... Bernhard Englitz
    Research Advance

    Animal behaviour alternates between stochastic exploration and goal-directed actions, which are generated by the underlying neural dynamics. Previously, we demonstrated that the compositional Restricted Boltzmann Machine (cRBM) can decompose whole-brain activity of larval zebrafish data at the neural level into a small number (∼100-200) of assemblies that can account for the stochasticity of the neural activity (van der Plas et al., eLife, 2023). Here, we advance this representation by extending to a combined stochastic-dynamical representation to account for both aspects using the recurrent temporal RBM (RTRBM) and transfer-learning based on the cRBM estimate. We demonstrate that the functional advantage of the RTRBM is captured in the temporal weights on the hidden units, representing neural assemblies, for both simulated and experimental data. Our results show that the temporal expansion outperforms the stochastic-only cRBM in terms of generalization error and achieves a more accurate representation of the moments in time. Lastly, we demonstrate that we can identify the original time-scale of assembly dynamics by estimating multiple RTRBMs at different temporal resolutions. Together, we propose that RTRBMs are a valuable tool for capturing the combined stochastic and time-predictive dynamics of large-scale data sets.