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

  • 4,129
    views
  • 621
    downloads
  • 99
    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
    Cameron T Ellis, Tristan S Yates ... Nicholas Turk-Browne
    Research Article

    Studying infant minds with movies is a promising way to increase engagement relative to traditional tasks. However, the spatial specificity and functional significance of movie-evoked activity in infants remains unclear. Here, we investigated what movies can reveal about the organization of the infant visual system. We collected fMRI data from 15 awake infants and toddlers aged 5–23 months who attentively watched a movie. The activity evoked by the movie reflected the functional profile of visual areas. Namely, homotopic areas from the two hemispheres responded similarly to the movie, whereas distinct areas responded dissimilarly, especially across dorsal and ventral visual cortex. Moreover, visual maps that typically require time-intensive and complicated retinotopic mapping could be predicted, albeit imprecisely, from movie-evoked activity in both data-driven analyses (i.e. independent component analysis) at the individual level and by using functional alignment into a common low-dimensional embedding to generalize across participants. These results suggest that the infant visual system is already structured to process dynamic, naturalistic information and that fine-grained cortical organization can be discovered from movie data.

    1. Neuroscience
    Diellor Basha, Amirmohammad Azarmehri ... Igor Timofeev
    Research Article

    Memory consolidation during sleep depends on the interregional coupling of slow waves, spindles, and sharp wave-ripples (SWRs), across the cortex, thalamus, and hippocampus. The reuniens nucleus of the thalamus, linking the medial prefrontal cortex (mPFC) and the hippocampus, may facilitate interregional coupling during sleep. To test this hypothesis, we used intracellular, extracellular unit and local field potential recordings in anesthetized and head restrained non-anesthetized cats as well as computational modelling. Electrical stimulation of the reuniens evoked both antidromic and orthodromic intracellular mPFC responses, consistent with bidirectional functional connectivity between mPFC, reuniens and hippocampus in anesthetized state. The major finding obtained from behaving animals is that at least during NREM sleep hippocampo-reuniens-mPFC form a functional loop. SWRs facilitate the triggering of thalamic spindles, which later reach neocortex. In return, transition to mPFC UP states increase the probability of hippocampal SWRs and later modulate spindle amplitude. During REM sleep hippocampal theta activity provides periodic locking of reuniens neuronal firing and strong crosscorrelation at LFP level, but the values of reuniens-mPFC crosscorrelation was relatively low and theta power at mPFC was low. The neural mass model of this network demonstrates that the strength of bidirectional hippocampo-thalamic connections determines the coupling of oscillations, suggesting a mechanistic link between synaptic weights and the propensity for interregional synchrony. Our results demonstrate the presence of functional connectivity in hippocampo-thalamo-cortical network, but the efficacy of this connectivity is modulated by behavioral state.