Non-canonical role for Lpar1-EGFP subplate neurons in early postnatal mouse somatosensory cortex

  1. Filippo Ghezzi
  2. Andre Marques-Smith
  3. Paul G Anastasiades
  4. Daniel Lyngholm
  5. Cristiana Vagnoni
  6. Alexandra Rowett
  7. Gokul Parameswaran
  8. Anna Hoerder-Suabedissen
  9. Yasushi Nakagawa
  10. Zoltan Molnar
  11. Simon J B Butt  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. University of Bristol, United Kingdom
  3. University of Minnesota Medical School, United States

Abstract

Subplate neurons (SPNs) are thought to play a role in nascent sensory processing in neocortex. To better understand how heterogeneity within this population relates to emergent function, we investigated the synaptic connectivity of Lpar1-EGFP SPNs through the first postnatal week in whisker somatosensory cortex (S1BF). These SPNs comprise of two morphological subtypes: fusiform SPNs with local axons, and pyramidal SPNs with axons that extend through the marginal zone. The former receive translaminar synaptic input up until the emergence of the whisker barrels; a timepoint coincident with significant cell death. In contrast, pyramidal SPNs receive local input from the subplate at early ages but then – during the later time window, acquire input from overlying cortex. Combined electrical and optogenetic activation of thalamic afferents identified that Lpar1-EGFP SPNs receive sparse thalamic innervation. These data reveal components of the postnatal network that interpret sparse thalamic input to direct the emergent columnar structure of S1BF.

Data availability

All data generated and analysed during this study are available via the University of Oxford open access data repository (https://ora.ox.ac.uk)

Article and author information

Author details

  1. Filippo Ghezzi

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Andre Marques-Smith

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6879-2858
  3. Paul G Anastasiades

    Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Daniel Lyngholm

    MRC Centre for Developmental Neurobiology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3708-0249
  5. Cristiana Vagnoni

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Alexandra Rowett

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Gokul Parameswaran

    MRC Centre for Developmental Neurobiology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Anna Hoerder-Suabedissen

    MRC Centre for Developmental Neurobiology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Yasushi Nakagawa

    Department of Neuroscience, University of Minnesota Medical School, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4876-5718
  10. Zoltan Molnar

    MRC Centre for Developmental Neurobiology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6852-6004
  11. Simon J B Butt

    Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
    For correspondence
    simon.butt@dpag.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2399-0102

Funding

Wellcome Trust (215199/Z/19/Z)

  • Filippo Ghezzi

Wellcome Trust (086362/Z/08/Z)

  • Andre Marques-Smith

Medical Research Council (MR/K004387/1)

  • Simon J B Butt

Human Frontiers Science Program Organisation (CDA0023/2008-C)

  • Simon J B Butt

Brain and Behavior Research Foundation (19079)

  • Simon J B Butt

Wellcome Trust (089286/Z/09/Z)

  • Simon J B Butt

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

Ethics

Animal experimentation: Animal care and experimental procedures were approved by the University of Oxford local ethical review committee and conducted in accordance with UK Home Office personal and project (70/6767; 30/3052; P861F9BB75) licenses under the Animals (Scientific Procedures) 1986 Act.

Copyright

© 2021, Ghezzi 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

  • 1,464
    views
  • 170
    downloads
  • 10
    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. Filippo Ghezzi
  2. Andre Marques-Smith
  3. Paul G Anastasiades
  4. Daniel Lyngholm
  5. Cristiana Vagnoni
  6. Alexandra Rowett
  7. Gokul Parameswaran
  8. Anna Hoerder-Suabedissen
  9. Yasushi Nakagawa
  10. Zoltan Molnar
  11. Simon J B Butt
(2021)
Non-canonical role for Lpar1-EGFP subplate neurons in early postnatal mouse somatosensory cortex
eLife 10:e60810.
https://doi.org/10.7554/eLife.60810

Share this article

https://doi.org/10.7554/eLife.60810

Further reading

    1. Neuroscience
    Ernie Yulyaningsih, Jung H Suh ... Pascal E Sanchez
    Research Article

    The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small-molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models – the optic nerve crush injury and an eIF2B loss of function (LOF) mutant – demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain-penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.

    1. Neuroscience
    Stefan Passlick, Ghanim Ullah, Christian Henneberger
    Research Article

    Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modeled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the mouse hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.