CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility.
Lindsay K FestaElena IrolloBrian J PlattYuzen TianStan FlorescoOlimpia MeucciPublished in: eLife (2020)
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.
Keyphrases
- cognitive decline
- prefrontal cortex
- cell migration
- mild cognitive impairment
- end stage renal disease
- oxidative stress
- newly diagnosed
- healthcare
- spinal cord
- ejection fraction
- public health
- chronic kidney disease
- antiretroviral therapy
- poor prognosis
- hiv positive
- hiv infected
- prognostic factors
- high glucose
- diabetic rats
- long non coding rna
- hiv aids
- endothelial cells
- risk assessment
- patient reported
- social media