Kir6.2构成的ATP敏感性钾通道在苯环己哌啶诱导的精神分裂症阴性症状中的作用(英文)  

Involvement of Kir6.2-composing ATP-sensitive Potassium Channels in Phencyclidine-induced Negative Symptoms of Schizophrenia

作　　者：戴婷[1] 陈中国[1] 段磊[1] 丁建花[1] 范益[1] 胡刚[1] 

机构地区：[1]南京医科大学药理学系江苏省神经退行性疾病重点实验室

出　　处：《神经药理学报》2011年第1期31-37,共7页Acta Neuropharmacologica

基　　金：国家自然科学基金重点项目(No.81030060)~~

摘　　要：目的:ATP敏感性钾(K-ATP)通道对多巴胺和谷氨酸能传导具有重要的调节作用,而多巴胺和谷氨酸能传导之间相互作用是精神分裂症病理机制的重要神经化学基础。因此,我们应用Kir6.2(主要表达在神经元的K-ATP亚基)敲除小鼠,通过苯环己哌啶诱导强迫游泳不动时间的延长,模拟精神分裂症的阴性症状,从而研究K-ATP通道在其中的作用。方法:连续注射14d苯环己哌啶(10 mg.kg-1,i.p.)后,通过观察强迫游泳实验中小鼠不动时间的长短,评价Kir6.2敲除对精神分裂症阴性症状中抑郁样表现的影响;应用高效液相色谱联合电化学检测法观察纹状体多巴胺及其代谢产物、多巴胺更新率的改变;应用溴脱氧尿嘧啶核苷插入法观察海马齿状回颗粒下区神经干细胞增殖的改变;应用Western blot技术观察磷酸化Akt水平的变化。结果:Kir6.2敲除取消了苯环己哌啶引起的强迫游泳不动时间的延长。不仅如此,Kir6.2敲除还抑制了苯环己哌啶诱导的纹状体多巴胺更新率的增加、海马齿状回颗粒下区神经干细胞增殖的减弱,以及磷酸化Akt水平升高。结论:Kir6.2组成的K-ATP通道参与了苯环己哌啶诱导的精神分裂症阴性症状,阻断K-ATP通道有望成为治疗精神分裂症的新策略。Objective： ATP-sensitive potassium（K-ATP） channels are crucial for dopaminergic and glutamatergic transmission,which has been demonstrated to be the important feature of pathophysiology in schizophrenia.We studied the effects of K-ATP channels on the phencyclidine（PCP）-induced changes in the forced swimming test（FST,an animal model of negative symptoms of schizophrenia）,using mice with knockout of the Kir6.2（a pore-forming subunit of neuronal K-ATP channel）.Methods： After repeated PCP（10 mg.kg-1,i.p.daily for 14days） administration,The FST were used to assess depression-related behaviors associated with negative symptoms.Striatal dopamine and dopamine turnover were measured by high pressure liquid chromatography with electrochemical detection.Cell proliferation in the subgranular zone（SGZ） was determined by bromodeoxyuridine immunohistochemistry.The expressions of total Akt and phosphorylation Akt were evaluated using Western blot.Results： After repeated PCP administration,the enhancement of immobility induced by the FST was attenuated in Kir6.2 knockout mice.Meanwhile,Kir6.2 knockout decreased striatal dopamine turnover,whereas wildtype mice exhibited an augmentation in response to PCP treatment.Furthermore,Kir6.2 knockout could prevent the inhibition of neural stem cell proliferation in the SGZ and suppressed the PCPinduced phosphorylation of AktSer473.Conclusion： These results suggest a possible implication of Kir6.2-composing K-ATP channels dysfunction in the pathogenesis of negative symptoms associated with schizophrenia.

关 键 词：ATP敏感性钾通道 苯环己哌啶 多巴胺 神经再生 精神分裂症 

分 类 号：R332[医药卫生—人体生理学]