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.
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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
