Department 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
Elena Irollo
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
Brian J Platt
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
Yuzen Tian
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, United States
Stan Floresco
Department of Psychology, University of British Columbia, Vancouver, Canada
Department 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 States
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.
