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目的自闭症发病率逐年上升,其与认知功能异常的神经环路失调关联性收到国内外研究者关注。然而,迄今仍未能阐明其确切病因和发病机制。我们以突触蛋白钙离子/钙调素依赖性蛋白激酶Ⅱ(Calcium/calmodulin-dependentprotein kinaseⅡ,CaMKⅡ)相关信号为切入点展开研究。方法 SD大鼠孕12.5 d时随机分为自闭症组和对照组,VPA水溶液(240 g.L-1)造模。检测子代大鼠的外观、睁眼时间、游泳平衡能力和自主活动情况;Western blotting、免疫荧光染色等技术研究海马突触CaMKⅡ/SynapsinⅠ/GluR1信息模块在自闭症模型脑组织中的表达情况,探讨其变化规律。结果自闭症模型大鼠发育缓慢、体型较小、毛发稀疏、短尾畸形,睁眼延迟,游泳能力低下;自主活动实验中表现为活动路程、活动时间和活动速度、边缘活动时间增加、中央活动时间、中央活动速度降低的自主活动增加和低探索性。Phos-pho-CaMKⅡ(Thr286),Phospho-SynapsinⅠ(Ser603),Phos-pho-GluR1(Ser831),Phospho-NR1(Ser896)在自闭症模型大鼠大脑皮层和海马部位的表达均有明显降低。免疫荧光染色也发现Phospho-CaMKⅡ(Thr286)在自闭症模型大鼠海马的阳性染色也明显降低。结论海马CaMKⅡ/SynapsinⅠ/GluR1信号紊乱与自闭症发病进程密切相关,关联深入研究将为预防和治疗自闭症的新药靶点发现提供实验依据。
Purpose The incidence of autism increased year by year, and its association with cognitive dysfunction of the neural circuit disorders received the attention of researchers at home and abroad. However, its exact etiology and pathogenesis have not yet been elucidated. We started with the relevant signals of Calcium / calmodulin-dependent protein kinase II (CaMKII). Methods SD rats were randomly divided into autism group and control group at 12.5 d of pregnancy, and VPA aqueous solution (240 g · L -1) was used to make model. Western blotting and immunofluorescence staining were used to detect the expression of synaptic CaMKⅡ / SynapsinⅠ / GluR1 in hippocampus in the brain of autism model rats , Discuss its change rule. Results The rats with autism developed slowly, with small size, sparse hair, short-tailed deformity, delayed opening of eyes, and poor swimming ability. The autonomic activity manifested as activity distance, activity time and activity speed, increased edge activity time, Activity time, reduced autonomy of central activities, increased activity and low exploratory. The expressions of Phos-pho-CaMKⅡ (Thr286), Phospho-SynapsinⅠ (Ser603), Phos-pho-GluR1 (Ser831) and Phospho-NR1 (Ser896) in the cerebral cortex and hippocampus of autistic rats were significantly decreased. Immunofluorescence staining also found that phosphorylation of Phospho-CaMKⅡ (Thr286) in the hippocampus of autistic model rats was also significantly lower. Conclusions The disturbance of CaMKⅡ / Synapsin Ⅰ / GluR1 signal in hippocampus is closely related to the pathogenesis of autism. The further study will provide experimental evidence for the discovery of new drug targets for the prevention and treatment of autism.