Objective To investigate the effect of thyroxine (T4)and donepezil (DON)treatment on the hypothy-roidism-induced alterations of ultrastructure and synaptotagmin-1 (syt-1 )expression in the hippocampus of adult rats.Methods Administration of 0.05% propylthiouracil (PTU)to drinking water for 6 weeks was used to repli-cate the model of hypothyroidism.From the 5th week,T4 group was given thyroxine (6 μg/100 g body weight )by intraperitoneal injection,DON group was given 0.005% DON in the drinking water,T4 +DON group was given a combination of both,the control and hypothyroid groups were given the same volume of saline solution by intraper-itoneal injection daily.The concentration of serum T3 and T4 was determined by radioimmunoassay kits,and the hippocampal ultrastructure was observed with transmission electron microscope (TEM)and the protein level of syt-1 was measured by Western blot.Results Compared to the control group,the concentration of serum T3 and T4 was significantly decreased in the hypothyroid group and the DON group (P <0.01),but returned to the normal in the T4 group or combined with DON group.TEMrevealed that signficant degeneration was in mitochondria and rar-efaction in free ribosomes of adult hpothyroid rats,synaptic structural damage and reduction of synaptic vesicles also appeared.The ultrastructural was partly restored by T4 or DON administration,but was completely restored by a combination of both treatments.Expression of syt-1 protein was significantly lower in hypothyroid rats compared with the controls (P <0.01 ),and was still expressed at lower level in hypothyroid treated with T4 alone (P <0.05),while was restored to normal values after co-administation of T4 and DON.Conclusion These observations indicate that adult hypothyroidism induces ultrastructural damage and a decrease of syt-1 proten in the hippocam-pus,and the alterations can not be restored by T4 monotherapy.In addition,the co-administration of T4 and DON result in more effective restoration than either alone.%目的：观察甲状腺素（T4）联合多奈哌齐（DON）治疗对成年期甲状腺功能减退症（简称甲减）大鼠海马内超微结构及突触结合蛋白 synaptotagmin-1（syt-1）表达的影响。方法饮0．05％丙基硫氧嘧啶（PTU）水建立成年期大鼠甲减模型共6周，第5周起，T4治疗组给予腹腔注射 T46μg／100 g 体重、DON 治疗组饮0．005％ DON 水，联合治疗组给予 T4＋DON 治疗，对照组及甲减组每日腹腔注射等量生理盐水。采用放射免疫法测定血清甲状腺素水平，透射电镜观察海马内超微结构，Western blot 方法分析海马内 syt-1的表达水平。结果甲减组、DON 治疗组大鼠血清甲状腺激素水平明显降低（P ＜0．01），T4治疗组、联合治疗组与对照组差异无统计学意义；电镜下甲减大鼠海马内神经元中线粒体呈现明显空泡变性、游离核糖体稀疏、突触结构受损、突触小泡数量减少，T4或 DON 治疗后上述损伤有所改善，而联合治疗恢复后表现最接近对照组；甲减大鼠海马内 syt-1蛋白表达量明显降低（P ＜0．01），单独 T4或 DON 治疗后表达仍下降（P ＜
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