1. Cell Biology
  2. Neuroscience
Download icon

Astrocytes refine cortical connectivity at dendritic spines

  1. W Christopher Risher
  2. Sagar Patel
  3. Il Hwan Kim
  4. Akiyoshi Uezu
  5. Srishti Bhagat
  6. Daniel K Wilton
  7. Louis-Jan Pilaz
  8. Jonnathan Singh Alvarado
  9. Osman Y Calhan
  10. Debra L Silver
  11. Beth Stevens
  12. Nicole Calakos
  13. Scott H Soderling
  14. Cagla Eroglu  Is a corresponding author
  1. Duke University Medical Center, United States
  2. Boston Children's Hospital, Harvard Medical School, United States
Research Article
  • Cited 61
  • Views 7,760
  • Annotations
Cite this article as: eLife 2014;3:e04047 doi: 10.7554/eLife.04047

Abstract

During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.

Article and author information

Author details

  1. W Christopher Risher

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sagar Patel

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Il Hwan Kim

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Akiyoshi Uezu

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Srishti Bhagat

    Department of Neurobiology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel K Wilton

    Department of Neurology, FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Louis-Jan Pilaz

    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jonnathan Singh Alvarado

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Osman Y Calhan

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Debra L Silver

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Beth Stevens

    Department of Neurology, FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Nicole Calakos

    Department of Neurobiology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Scott H Soderling

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Cagla Eroglu

    Department of Cell Biology, Duke University Medical Center, Durham, United States
    For correspondence
    c.eroglu@cellbio.duke.edu
    Competing interests
    The authors declare that no competing interests exist.

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) protocol (# A195-11-08) of Duke University Medical Center. The mice were euthanized by following the approved protocols which were performed under avertin anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Liqun Luo, Howard Hughes Medical Institute, Stanford University, United States

Publication history

  1. Received: July 16, 2014
  2. Accepted: December 16, 2014
  3. Accepted Manuscript published: December 17, 2014 (version 1)
  4. Version of Record published: January 8, 2015 (version 2)

Copyright

© 2014, Risher 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

  • 7,760
    Page views
  • 1,439
    Downloads
  • 61
    Citations

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

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
    Friederike Elisabeth Kohrs et al.
    Tools and Resources

    Rab GTPases are molecular switches that regulate membrane trafficking in all cells. Neurons have particular demands on membrane trafficking and express numerous Rab GTPases of unknown function. Here we report the generation and characterization of molecularly defined null mutants for all 26 rab genes in Drosophila. In flies, all rab genes are expressed in the nervous system where at least half exhibit particularly high levels compared to other tissues. Surprisingly, loss of any of these 13 nervous system-enriched Rabs yielded viable and fertile flies without obvious morphological defects. However, all 13 mutants differentially affected development when challenged with different temperatures, or neuronal function when challenged with continuous stimulation. We identified a synaptic maintenance defect following continuous stimulation for six mutants, including an autophagy-independent role of rab26. The complete mutant collection generated in this study provides a basis for further comprehensive studies of Rab GTPases during development and function in vivo.

    1. Cell Biology
    Luca Minati et al.
    Tools and Resources Updated

    A vast portion of the mammalian genome is transcribed as long non-coding RNAs (lncRNAs) acting in the cytoplasm with largely unknown functions. Surprisingly, lncRNAs have been shown to interact with ribosomes, encode peptides, or act as ribosome sponges. These functions still remain mostly undetected and understudied owing to the lack of efficient tools for genome-wide simultaneous identification of ribosome-associated and peptide-producing lncRNAs. Here, we present AHA-mediated RIBOsome isolation (AHARIBO), a method for the detection of lncRNAs either untranslated, but associated with ribosomes, or encoding small peptides. Using AHARIBO in mouse embryonic stem cells during neuronal differentiation, we isolated ribosome-protected RNA fragments, translated RNAs, and corresponding de novo synthesized peptides. Besides identifying mRNAs under active translation and associated ribosomes, we found and distinguished lncRNAs acting as ribosome sponges or encoding micropeptides, laying the ground for a better functional understanding of hundreds of lncRNAs.