Increased synapse elimination by inflammatory cells contributes to long-lasting post-stroke memory dysfunction in old mice — UCSF

Background Post-stroke memory dysfunction is common in elderly people. We showed previously that a bone fracture (BF) shortly before ischemic stroke also caused long-lasting memory dysfunction in young mice, and inhibition of inflammation by α7-nicotinic acetylcholine receptor (α7-nAChR) agonist treatment alleviated their cognitive deficit. Excessive synapse removal by glial cells contributes to neuronal network disruption and neurobehavioral deficits during the acute and subacute stages of stroke. However, its role at the chronic stage of stroke remains unclear. In this study, we analyzed the impact of microglia- and astrocyte-mediated synapse removal at the chronic stage of ischemic stroke on memory function and synapse structure in young (2-month-old) and old mice (15-18-month-old). We also tested whether α7-nAChR agonist treatment reduced synapse loss in young mice with BF+stroke. Methods Ischemic stroke was induced by permanent occlusion of the distal middle cerebral artery (dMCAO). The BF model was induced by creating a tibia fracture under aseptic conditions 6 h before dMCAO. An α7-nAChR agonist was administered immediately before BF and 1 day after dMCAO. Memory function was evaluated weekly for 8 weeks using the Y-maze test and the novel object recognition test one week before and 8 weeks after dMCAO. Atrophic volumes, synapse-engulfing astrocytes and microglia/macrophages, RNA expression profiles, neurite length, and dendritic spine density were analyzed in the peri-atrophic regions and hippocampal regions eight weeks after dMCAO. Results Old mice developed long-lasting memory dysfunction (> eight weeks), had larger atrophic volumes, shorter neurite length, and fewer dendritic spines, accompanied by increased synapse-engulfing astrocytes and microglia/macrophages in the peri-atrophic and hippocampal regions than young stroke-only mice. Old stroke mice showed higher upregulation of inflammatory pathways and more downregulation of neurite growth and synaptic transmission pathways than in young stroke-only mice. Young mice with BF+stroke had more synapse-engulfing astrocytes and microglia/macrophages in the hippocampal regions than in young stroke-only mice. An α7-nAChR agonist treatment reduced synapse-engulfing microglia/macrophages and astrocytes in the hippocampi of BF+stroke mice. Conclusions Enhanced synapse elimination contributes to the long-lasting post-stroke memory dysfunction. Inhibition of neuroinflammation at the early stage of stroke can reduce synapse loss and improve post-stroke memory function.