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.