Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB.T1

  1. Leanne M Holt
  2. Raymundo D Hernandez
  3. Natasha L Pacheco
  4. Beatriz Torres Ceja
  5. Muhannah Hossain
  6. Michelle Olsen  Is a corresponding author
  1. University of Alabama at Birmingham, United States
  2. Virginia Polytechnic Institute and State University, United States

Abstract

Brain derived neurotrophic factor (BDNF) is a critical growth factor involved in the maturation of the CNS, including neuronal morphology and synapse refinement. Herein, we demonstrate astrocytes express high levels of BDNF's receptor, TrkB (in the top 20 of protein-coding transcripts), with nearly exclusive expression of the truncated isoform, TrkB.T1, which peaks in expression during astrocyte morphological maturation. Using a novel culture paradigm, we show that astrocyte morphological complexity is increased in the presence of BDNF and is dependent upon BDNF/TrkB.T1 signaling. Deletion of TrkB.T1, globally and astrocyte-specifically, in mice revealed morphologically immature astrocytes with significantly reduced volume, as well as dysregulated expression of perisynaptic genes associated with mature astrocyte function. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis or function. These data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphological maturation, a critical process for CNS development.

Data availability

Sequencing data have been deposited in GEO under accession code GSE122176.

The following data sets were generated

Article and author information

Author details

  1. Leanne M Holt

    Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Raymundo D Hernandez

    School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Natasha L Pacheco

    Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9617-8887
  4. Beatriz Torres Ceja

    School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Muhannah Hossain

    School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michelle Olsen

    School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, United States
    For correspondence
    molsen1@vt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1394-664X

Funding

National Institute of Neurological Disorders and Stroke (F31NS100259)

  • Leanne M Holt

National Institute of Neurological Disorders and Stroke (R01NS075062)

  • Michelle Olsen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Cagla Eroglu, Duke University, United States

Ethics

Animal experimentation: All experiments were performed according to NIH guidelines and with approval from the Animal Care and Use Committee of the University of Alabama at Birmingham (#20650) and Virginia Polytechnic Institute and State University (#17-012). Every effort was made to minimize pain and discomfort.

Version history

  1. Received: December 22, 2018
  2. Accepted: August 20, 2019
  3. Accepted Manuscript published: August 21, 2019 (version 1)
  4. Version of Record published: September 4, 2019 (version 2)
  5. Version of Record updated: March 19, 2021 (version 3)

Copyright

© 2019, Holt 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

  • 5,809
    views
  • 778
    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. Leanne M Holt
  2. Raymundo D Hernandez
  3. Natasha L Pacheco
  4. Beatriz Torres Ceja
  5. Muhannah Hossain
  6. Michelle Olsen
(2019)
Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB.T1
eLife 8:e44667.
https://doi.org/10.7554/eLife.44667

Share this article

https://doi.org/10.7554/eLife.44667

Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Maximilian Nagel, Marco Niestroj ... Marc Spehr
    Research Article

    In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health, and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex/strain-selective ‘raw’ chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animal’s sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary ‘secretome’, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.

    1. Neuroscience
    Kenta Abe, Yuki Kambe ... Tatsuo Sato
    Research Article

    Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse activity in dopamine axons responsive to both reward and aversive stimuli. Some axons exhibited a preference for reward, while others favored aversive stimuli, and there was a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day.