Abstract TP088: Decreased axonal outgrowth and dendritic plasticity, and increased synaptic removal in hippocampal and cortical neurons contribute to the long-lasting post-stroke memory dysfunction in old mice

Background and Purpose: Long-term memory dysfunction is more common in old patients than young patients after a stroke. Ischemia-induced white matter and dendritic plasticity damage are correlated with poor neurological outcomes in stroke patients. Inflammation-mediated synapse elimination is evident in acute and sub-acute stages after stroke. Hypothesis: Excessive reduction of axonal outgrowth and dendritic plasticity in hippocampal and cortical neurons, accompanied by enhanced neuroinflammation-mediated synapse removal, contributes to the long-lasting post-stroke memory dysfunction in old subjects. Methods: Ischemic stroke was induced in young and old mice. Memory functions were monitored by using the Y-maze test weekly for 8 weeks and the novel object recognition (NOR) test at 7 days before and 8 weeks post-stroke. Brains were collected 8 weeks after the induction of ischemic stroke to study transcriptome changes by RNAseq and neuronal injuries using Golgi staining combined with Sholl analysis. Results: Old mice developed long-term memory dysfunction after ischemic stroke, larger infarct volumes than young mice. Old mice exhibited shorter neurite length, fewer neurites, and dendritic spines in the peri-atrophic region and ipsilateral hippocampal neurons in the CA1, CA2, CA3, and dentate gyrus (DG) regions compared to the young mice. Sholl analysis showed that the dendrites of neurons in the cortical and hippocampal regions of old mice have shorter radial distances (fewer intersections) than those in young mice and their contralateral counterparts. Go analyses showed that after ischemic stroke injury, the inflammatory pathways and antioxidant activity were increased in the ipsilateral cortex of old mice than young mice. The chemokine signaling, inflammatory, and complement pathways were upregulated, while axon guidance was downregulated in the ipsilateral hippocampi of old mice than young mice and the old contralateral hippocampus. The expressions of genes involved in axonal guidance, P311, Gpr17, and Nr4a3, were downregulated in the old ischemic cortex compared to the young mice. Gpr17 was also downregulated in the old ipsilateral hippocampus compared to the young. Conclusion: Hindered axonal regeneration and dendritic remodeling contribute to long-lasting post-stroke memory dysfunction in old mice. Therefore, the reduction of neuronal damage through neuroprotective agents may reduce long-lasting post-stroke memory dysfunction in old patients.