1. Developmental Biology
  2. Neuroscience
Download icon

Activity-dependent modulation of synapse-regulating genes in astrocytes

  1. Isabella Farhy-Tselnicker
  2. Matthew M Boisvert
  3. Hanqing Liu
  4. Cari Dowling
  5. Galina A Erikson
  6. Elena Blanco-Suarez
  7. Chen Farhy
  8. Maxim N Shokhirev
  9. Joseph R Ecker
  10. Nicola J Allen  Is a corresponding author
  1. Salk Institute for Biological Studies, United States
  2. Thomas Jefferson University, United States
  3. Sanford Burnham Prebys Medical Discovery Institute, United States
  4. The Salk Institute for Biological Studies, United States
  5. Howard Hughes Medical Institute, Salk Institute for Biological Studies, United States
Research Article
  • Cited 0
  • Views 726
  • Annotations
Cite this article as: eLife 2021;10:e70514 doi: 10.7554/eLife.70514

Abstract

Astrocytes regulate the formation and function of neuronal synapses via multiple signals, however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually-evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development are also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders.

Data availability

DATA AVAILABILITYAll data supporting the results of this study can be found in the following locations:Processed RNA sequencing data presented in Figure 1 is available in Figure 1- Source Data 1.Data presented in graphs in Figures 2-5 is available in Figure 2-5 Source Data files.Processed single nucleus RNA sequencing data presented in Figure 6 is available in Figure 6-Source Data 1.The RNA sequencing data has been deposited at GEO. Ribotag data is available at GSE161398 and glial snRNAseq at GSE163775.Processed RNA sequencing data is available in a searchable format at the following web locations:Ribotag astrocyte developmental dataset:igc1.salk.edu:3838/astrocyte_transcriptomeSingle nucleus glial cell sequencing:mouse-astro-dev.cells.ucsc.edu

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Isabella Farhy-Tselnicker

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3733-7120
  2. Matthew M Boisvert

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Hanqing Liu

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cari Dowling

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Galina A Erikson

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Elena Blanco-Suarez

    Neuroscience, Thomas Jefferson University, PHILADELPHIA, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2131-6376
  7. Chen Farhy

    Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6160-3479
  8. Maxim N Shokhirev

    The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Joseph R Ecker

    Plant Biology Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5799-5895
  10. Nicola J Allen

    Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    nallen@salk.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7542-5930

Funding

National Institutes of Health (NS105742)

  • Nicola J Allen

National Institutes of Health (NS089791)

  • Nicola J Allen

Pew Charitable Trusts

  • Nicola J Allen

Chan Zuckerberg Initiative (2018-191894)

  • Nicola J Allen

Howard Hughes Medical Institute

  • Joseph R Ecker

National Institutes of Health (NIH NCI CCSG P30 014195)

  • Maxim N Shokhirev

Hearst Foundations

  • Nicola J Allen

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 accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal work was approved by the Salk Institute Institutional Animal Care and Use Committee (IACUC) protocol 12-00023.

Reviewing Editor

  1. Beth Stevens, Boston Children's Hospital, United States

Publication history

  1. Received: May 19, 2021
  2. Accepted: September 7, 2021
  3. Accepted Manuscript published: September 8, 2021 (version 1)

Copyright

© 2021, Farhy-Tselnicker 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

  • 726
    Page views
  • 174
    Downloads
  • 0
    Citations

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

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. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Alessandro Bonfini et al.
    Research Article

    The gut is the primary interface between an animal and food, but how it adapts to qualitative dietary variation is poorly defined. We find that the Drosophila midgut plastically resizes following changes in dietary composition. A panel of nutrients collectively promote gut growth, which sugar opposes. Diet influences absolute and relative levels of enterocyte loss and stem cell proliferation, which together determine cell numbers. Diet also influences enterocyte size. A high sugar diet inhibits translation and uncouples ISC proliferation from expression of niche-derived signals but, surprisingly, rescuing these effects genetically was not sufficient to modify diet's impact on midgut size. However, when stem cell proliferation was deficient, diet's impact on enterocyte size was enhanced, and reducing enterocyte-autonomous TOR signaling was sufficient to attenuate diet-dependent midgut resizing. These data clarify the complex relationships between nutrition, epithelial dynamics, and cell size, and reveal a new mode of plastic, diet-dependent organ resizing.

    1. Developmental Biology
    2. Physics of Living Systems
    Yonghyun Song, Changbong Hyeon
    Research Article Updated

    Spatial boundaries formed during animal development originate from the pre-patterning of tissues by signaling molecules, called morphogens. The accuracy of boundary location is limited by the fluctuations of morphogen concentration that thresholds the expression level of target gene. Producing more morphogen molecules, which gives rise to smaller relative fluctuations, would better serve to shape more precise target boundaries; however, it incurs more thermodynamic cost. In the classical diffusion-depletion model of morphogen profile formation, the morphogen molecules synthesized from a local source display an exponentially decaying concentration profile with a characteristic length λ. Our theory suggests that in order to attain a precise profile with the minimal cost, λ should be roughly half the distance to the target boundary position from the source. Remarkably, we find that the profiles of morphogens that pattern the Drosophila embryo and wing imaginal disk are formed with nearly optimal λ. Our finding underscores the cost-effectiveness of precise morphogen profile formation in Drosophila development.