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Objective To investigate the effect of cocaine and amphetamine-regulated transcript (CART ) peptides on cortical synaptic plasticity in ischemia-reperfusion (I/R ) injury mice. Methods A total of 288 healthy male specific pathogen free(SPF)grade Kunming mice aged 0 to 12 weeks were selected. They were divided into four groups:I/R group (n =81 ),I/R +CART group (n =81),sham operation group (n=63),and sham operation+CART group (n=63)according to the random number table method. A model of middle cerebral artery occlusion (MCAO)for 2 h and reperfusion was induced. Before reperfusion,the mice of the I/R+CART group were injected CART via tail vein (0. 5μg, 200μl)and the those of the sham operation+CART group were injected equal CART;repeated administration once every 24 hours. 2,3,5-Triphenyl tetrazolium chloride assay was used to detect cerebral infarction volume of the I/R group and the I/R+CART group at different time points (24 h,72 h,and day 7 )after achieving reperfusion. The transmission electron microscope was used to observe the ultrastructural changes of synapses at different time points,and the synaptic morphological parameters were analyzed quantitatively. Western blot was used to observe the expression level of postsynaptic density 95 (PSD-95)proteins in the surrounding area of cortical infarct at 72 h after reperfusion. Results (1 )Compared with the sham operation group,the number of synapses was significantly decreased in the cortical slices in the I/R group (3. 37 ± 0. 38μm2 vs. 7. 04 ± 0. 55μm2 ,2. 89 ± 0. 22μm2 vs. 6. 89 ± 0. 04μm2 ,3. 25 ± 0. 18μm2 vs. 6. 78 ± 0. 42μm2;all P<0. 05). The density of PSD was significantly decreased (24. 4 ± 2. 8 nm vs. 47. 3 ± 6. 1 nm,23. 8 ± 3. 7 nm vs. 46. 5 ± 7. 5 nm,24. 6 ± 2. 2 nm vs. 48. 1 ± 5. 1 nm;all P <0. 05). The width of synaptic cleft was increased (25. 2 ± 2. 1 nm vs. 21. 5 ± 1. 6 nm,25. 2 ± 1. 4 nm vs. 21. 3 ± 1. 0 nm,23. 7 ± 2. 6 nm vs. 21. 6 ± 1. 6 nm;all P<0. 05). The expression level of PSD-95 protein was decreased at 72 h after reperfusion (P<0. 05). (2)Compared with the I/R group,the infarction volume of the I/R+CART group was significantly reduced at 24 h,72 h,and day 7 after reperfusion (29. 0 ± 1. 9% vs. 36. 3 ± 1. 4%,38. 1 ± 1. 4% vs. 47. 6 ± 2. 7%,and 36. 0 ± 2. 8% vs. 42. 5 ± 2. 0%,respectively;all P<0. 05). The number of synapses was significantly increased (4. 32 ± 0. 35 μm2 )and the expression level of PSD-95 protein was increased at 72 h after reperfusion (P<0. 05). The PSD density (33. 8 ± 3. 4,34. 2 ± 4. 6,38. 2 ± 4. 0 nm)was thickened at 24 h,72 h,and day 7 after reperfusion (all P <0. 05),and there were no significant differences in the width of synaptic cleft at each time point(allP>0.05).Conclusion CART can reduce cerebral infarct volume of I/R in mice and improve synaptic plasticity of cortical neurons in mice after ischemic injury.