CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility
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 syn...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/49717 |
| _version_ | 1811180533559853056 |
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| author | Lindsay K Festa Elena Irollo Brian J Platt Yuzen Tian Stan Floresco Olimpia Meucci |
| author_facet | Lindsay K Festa Elena Irollo Brian J Platt Yuzen Tian Stan Floresco Olimpia Meucci |
| author_sort | Lindsay K Festa |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:04:39Z |
| format | Article |
| id | doaj.art-3b5f7f7602cd410bb2d8ece82693d122 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:04:39Z |
| publishDate | 2020-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3b5f7f7602cd410bb2d8ece82693d1222022-12-22T04:32:40ZengeLife Sciences Publications LtdeLife2050-084X2020-01-01910.7554/eLife.49717CXCL12-induced rescue of cortical dendritic spines and cognitive flexibilityLindsay K Festa0https://orcid.org/0000-0002-5419-9532Elena Irollo1Brian J Platt2Yuzen Tian3Stan Floresco4Olimpia Meucci5https://orcid.org/0000-0001-8333-4804Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States; Center of Neuroimmunology and CNS Therapeutics, Institute of Molecular Medicine and Infectious Diseases, Drexel University College of Medicine, Philadelphia, United StatesDepartment of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United StatesDepartment of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United StatesDepartment of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United StatesDepartment of Psychology, University of British Columbia, Vancouver, CanadaDepartment of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States; Center of Neuroimmunology and CNS Therapeutics, Institute of Molecular Medicine and Infectious Diseases, Drexel University College of Medicine, Philadelphia, United States; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, United StatesSynaptodendritic 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.https://elifesciences.org/articles/49717chemokineprefrontal cortexcognitive declineneuroHIV |
| spellingShingle | Lindsay K Festa Elena Irollo Brian J Platt Yuzen Tian Stan Floresco Olimpia Meucci CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility eLife chemokine prefrontal cortex cognitive decline neuroHIV |
| title | CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility |
| title_full | CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility |
| title_fullStr | CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility |
| title_full_unstemmed | CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility |
| title_short | CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility |
| title_sort | cxcl12 induced rescue of cortical dendritic spines and cognitive flexibility |
| topic | chemokine prefrontal cortex cognitive decline neuroHIV |
| url | https://elifesciences.org/articles/49717 |
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