CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility

  1. Lindsay K Festa
  2. Elena Irollo
  3. Brian J Platt
  4. Yuzen Tian
  5. Stan Floresco
  6. Olimpia Meucci  Is a corresponding author
  1. Drexel University College of Medicine, United States
  2. University of British Columbia, Canada

Abstract

Synaptodendritic pruning is a common cause of cognitive decline in neurological disorders, including HIV-associated neurocognitive disorders (HAND). HAND persists in treated patients as a result of chronic inflammation and low-level expression of viral proteins, though the mechanisms involved in synaptic damage are unclear. Here, we report that the chemokine CXCL12 recoups both cognitive performance and synaptodendritic health in a rodent model of HAND, which recapitulates the neuroinflammatory state of virally controlled individuals and the associated structural/functional deficiencies. CXCL12 preferentially regulates plastic thin spines on layer II/III pyramidal neurons of the medial prefrontal cortex via CXCR4-dependent stimulation of the Rac1/PAK actin polymerization pathway, leading to increased spine density and improved flexible behavior. Our studies unveil a critical role of CXCL12/CXCR4 signaling in spine dynamics and cognitive flexibility, suggesting that HAND - or other diseases driven by spine loss - may be reversible and upturned by targeting Rac1-dependent processes in cortical neurons.

Data availability

All data presented in this manuscript are available as source data files.

Article and author information

Author details

  1. Lindsay K Festa

    Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5419-9532
  2. Elena Irollo

    Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Brian J Platt

    Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuzen Tian

    Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stan Floresco

    Department of Psychology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Olimpia Meucci

    Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
    For correspondence
    om29@drexel.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8333-4804

Funding

National Institute on Drug Abuse (DA015014)

  • Olimpia Meucci

National Institute on Drug Abuse (DA032444)

  • Olimpia Meucci

National Institute on Drug Abuse (DA040519)

  • Olimpia Meucci

National Institute of Mental Health (MH078795)

  • Lindsay K Festa

Natural Sciences and Engineering Research Council of Canada

  • Stan Floresco

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 using rats singly housed in isolation in our Association for Assessment and Accreditation of Laboratory Animal Care-accredited barrier facilities in accordance with the National Institutes of Health guidelines and institutional approval by the Institutional Animal Care and Use Committee (Drexel University protocol #20733 and 20732).

Reviewing Editor

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

Publication history

  1. Received: August 12, 2019
  2. Accepted: January 21, 2020
  3. Accepted Manuscript published: January 23, 2020 (version 1)
  4. Version of Record published: February 7, 2020 (version 2)

Copyright

© 2020, Festa 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.

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  1. Lindsay K Festa
  2. Elena Irollo
  3. Brian J Platt
  4. Yuzen Tian
  5. Stan Floresco
  6. Olimpia Meucci
(2020)
CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility
eLife 9:e49717.
https://doi.org/10.7554/eLife.49717
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