CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility
- Drexel University College of Medicine, United States
- 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
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).
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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CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility
eLife 9:e49717.
https://doi.org/10.7554/eLife.49717
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