Increased Synapse Elimination by Inflammatory Cells Contributes to Long-lasting Post-Stroke Memory Dysfunction in Old Mice

Shabani, Z.; Pan, P.; Li, Q.; Wang, Z.; Leng, K.; Sangras, S.; Huo, K.; Yadav, A.; Wang, C.; Shi, J.; Chinn, G.; Kyritsis, N.; Ferguson, A. R.; Hellman, J.; Su, H.

doi:10.1101/2025.06.13.659591

bioRxiv · 10.1101/2025.06.13.659591

Increased Synapse Elimination by Inflammatory Cells Contributes to Long-lasting Post-Stroke Memory Dysfunction in Old Mice

Shabani, Z.·Pan, P.·Li, Q.·Wang, Z.·Leng, K.·Sangras, S.·Huo, K.·Yadav, A.·Wang, C.·Shi, J.·Chinn, G.·Kyritsis, N.·Ferguson, A. R.·Hellman, J.·Su, H.

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Abstract

Old patients are more likely to experience memory dysfunction than young patients after a stroke. It has been reported that brain astrocytes and microglia cause excessive removal of synapses at the acute and subacute stages of stroke, and inhibition of their phagocytosis improved neurobehavioral outcomes. We hypothesized that memory dysfunction in old subjects is associated with increased synapse removal by inflammatory cells. Ischemic stroke was induced in young (2-month-old) and old (15-18-month-old) mice. Memory functions were analyzed by the Y-maze test weekly for 8 weeks and the novel object recognition (NOR) test at 7 days before and 8 weeks post-stroke. We have also created a tibia fracture 6 hours before stroke injury in young mice, to test if the activation of 7-nicotinic acetylcholine receptor (nAchRs) reduces inflammatory cells and synapse elimination. Brains were collected 8 weeks after the induction of ischemic stroke. Transcriptome changes, neuronal injuries, neuroinflammation, synapse removal, and neurite outgrowth were analyzed. We found that old mice developed long-term memory dysfunction after ischemic stroke, which was not seen in young mice. Old mice showed larger infarct volume, higher neuroinflammation, and more synapses engulfed by microglia/macrophages and astrocytes in the peri-atrophic region and hippocampi than young mice. More synapse-engulfing astrocytes than microglia/macrophages were present in the peri-atrophic region and the ipsilateral hippocampi, suggesting that reactive astrocytes contributed more than activated microglia/macrophages in synapse removal. Activation of 7-nAchRs in mice subjected to tibia fracture 6 hours before ischemic injury reduced synapse removal by microglia/macrophages and astrocytes in the hippocampi. Our study indicated that an increase in synaptic elements by inflammatory cells contributes to the long-lasting memory deficit after stroke in old mice. Astrocytes may contribute more than microglia/macrophages in synapse removal. Inhibition of neuroinflammation by activating 7-nAchRs can reduce synapse loss and thus may improve post-stroke memory function.

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Shabani, Z., Pan, P., Li, Q., Wang, Z., Leng, K., Sangras, S., Huo, K., Yadav, A., Wang, C., Shi, J., Chinn, G., Kyritsis, N., Ferguson, A. R., Hellman, J., Su, H.. 2025-06-15. Increased Synapse Elimination by Inflammatory Cells Contributes to Long-lasting Post-Stroke Memory Dysfunction in Old Mice. https://doi.org/10.1101/2025.06.13.659591

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