Multiple Mild Stimulations Reduce Membrane Distribution of CX3CR1 Promoted by Annexin al in Microglia to Attenuate Excessive Dendritic Spine Pruning and Cognitive Deficits Caused by a Transient Ischemic Attack in Mice

A transient ischemic attack(TIA)can cause reversible and delayed impairment of cognition,but the specific mechanisms arestill unclear.Annexin al(ANXA1)is a phospholipid-binding protein.Here,we confirmed that cognition and hippocampal synapses were impaired in TIA-treated mice,and this could be rescued by multiple mild stimulations(MMS).TIA promoted the interaction of ANXAl and CX3CR1,increased the membrane distribution of CX3CR1 in microglila,and thus enhanced the CX3CR1 and CX3CL1 interaction.These phenomena induced by TIA could be reversed by MMS.Meanwhile,the CX3CR1 membrane distribution and CX3CR1-CX3CL1 interaction were upregulated in primary cultured microglia overexpressing ANXAl,and the spine density was significantly reduced in co-cultured microglia overexpressing ANXAl and neurons.Moreover,ANXAl overexpression in microglia abolished the protection of MMS after TIA.Collectively,our study provides a potential strategy for treating the delayed synaptic injury caused by TIA.