本文選題：MK-801 + 認(rèn)知功能損傷��； 參考：《復(fù)旦大學(xué)》2013年博士論文

【摘要】：第一部分 MK-801對青春期大鼠認(rèn)知功能和海馬神經(jīng)細(xì)胞突觸的影響 背景：認(rèn)知障礙是精神分裂癥的核心癥狀之一。研究發(fā)現(xiàn)突觸生長缺陷與認(rèn)知障礙有關(guān)。尸檢研究也發(fā)現(xiàn)精神分裂癥患者海馬神經(jīng)細(xì)胞也存在突觸生長缺陷。NMDA受體在青春期大腦發(fā)育的關(guān)鍵時期通過調(diào)節(jié)突觸修剪和穩(wěn)定而對大腦發(fā)育起了關(guān)鍵作用。非競爭性NMDA受體阻斷劑常被用來制作精神分裂癥認(rèn)知障礙動物模型。 目的：探索青春發(fā)育期阻斷NMDA受體是否會導(dǎo)致海馬神經(jīng)細(xì)胞的突觸生長缺陷,并最終導(dǎo)致認(rèn)知障礙。方法：雄性青春期大鼠接受14天MK-801(0.2mg/kg i.p qd)或相等容積的生理鹽水的腹腔注射后,觀察它們的空間記憶能力、樹突棘形態(tài)變化、突觸前和突觸后標(biāo)志物(SYP和PSD-95)的蛋白表達(dá)量以及突觸生長相關(guān)因子RhoA、Rac1和Cdc42基因表達(dá)水平的變化。 結(jié)果：我們發(fā)現(xiàn)亞慢性MK-801使青春期大鼠認(rèn)知功能損傷,海馬神經(jīng)細(xì)胞的樹突棘頭直徑縮小。同時,亞慢性MK-801使青春期大鼠海馬神經(jīng)細(xì)胞內(nèi)的突觸素和PSD-95的蛋白表達(dá)量明顯下降,RhoA mRNA表達(dá)水平上升但是Rac1和Cdc42的mRNA水平明顯下降。 結(jié)論：青春發(fā)育期如果NMDA受體受到阻斷會導(dǎo)致海馬神經(jīng)細(xì)胞的突觸生長缺陷這次的研究結(jié)果為探索精神分裂癥認(rèn)知障礙的發(fā)病機(jī)制提供了一個新的研究方向。 第二部分 奧氮平、利培酮和喹硫平對MK-801精神分裂癥模型大鼠認(rèn)知和海馬小清蛋白陽性中間神經(jīng)元的影響 背景：認(rèn)知障礙是精神分裂癥的核心癥狀之一。非經(jīng)典抗精神病藥物能用來治療認(rèn)知障礙。但是非經(jīng)典抗精神病藥物(APDs)改善認(rèn)知損傷的機(jī)制至今不明。尸檢和關(guān)聯(lián)研究均證明PV中間神經(jīng)元的突觸抑制功能障礙與精神分裂癥患者認(rèn)知障礙密切相關(guān)。亞慢性MK-801能誘導(dǎo)青春期大鼠出現(xiàn)類似于精神分裂癥認(rèn)知障礙癥狀和PV中間神經(jīng)元數(shù)量下降等神經(jīng)病理學(xué)改變。 目的：選擇臨床常用的奧氮平、利培酮和喹硫平這三種APDs,作用于MK-801模擬分裂癥認(rèn)知損傷模型大鼠,觀察大鼠的空間記憶認(rèn)知功能和海馬小清蛋白中間神經(jīng)元密度的改變。 方法：40只青春期雄性大鼠隨機(jī)分成5組(n=8)：對照組、MK-801組、奧氮平組、利培酮組、喹硫平組。對照組接受生理鹽水(1ml/kg i.p qd)14天,其余大鼠接受MK-801(0.2mg/kg i.p qd)14天。造模結(jié)束24小時后,對照組和MK-801組大鼠蒸餾水灌胃(1ml/Kgi.g qd),其余三組分別接受奧氮平(2.5mg/kg ig qd)、利培酮(1mg/kg ig qd)口喹硫平(25mg/kg ig qd)給藥10天。之后利用水迷宮試驗測量大鼠空間記憶能力和游泳速度,通過免疫組化方法檢測海馬PV陽性細(xì)胞密度。 結(jié)果：研究結(jié)果顯示,MK-801造成青春期大鼠認(rèn)知功能的損傷和腦海馬區(qū)PV中間神經(jīng)元數(shù)量的下降。利培酮和喹硫平能緩解MK-801造成的空間記憶方面的認(rèn)知損傷和海馬區(qū)PV中間神經(jīng)元減少。 結(jié)論：保護(hù)海馬區(qū)PV中間神經(jīng)元可能是非經(jīng)典APDs改善精神分裂癥患者的空間記憶方面的認(rèn)知損傷的重要機(jī)制。 第三部分 喹硫平通過激活5-HT1a突觸前受體改善MK-801誘導(dǎo)的認(rèn)知損傷 背景：目前認(rèn)知障礙的治療已經(jīng)成為精神科臨床治療的重點。非經(jīng)典APDs能用來治療認(rèn)知障礙。但是非經(jīng)典APDs改善認(rèn)知損傷的機(jī)制至今不明。尸檢研究發(fā)現(xiàn)精神分裂癥患者腦內(nèi)的5-HT1a受體密度上升,這說明5HT1a受體功能異常。既往在精神病學(xué)領(lǐng)域關(guān)于5-HTla受體的研究多集中在情緒障礙方面,最近幾年5-HT1a受體與認(rèn)知功能的關(guān)聯(lián)受到越來越多的關(guān)注。非經(jīng)典APDs很可能通過影響5-HT1a受體功能來改善認(rèn)知。喹硫平是5-HT.1a受體部分激動劑,對精神分裂癥認(rèn)知障礙有出色的療效。另外,PKA是5-HT1a受體介導(dǎo)的最經(jīng)典的信號傳導(dǎo)通路cAMP-PKA通路中最重要的信號因子之一,對認(rèn)知功能有著重要的調(diào)節(jié)作用。5-HT1a突觸前受體被激活時導(dǎo)致PKA活性上升,而5-HT1a突觸后受體被激活時導(dǎo)致PKA活性下降。 目的：利用精神分裂癥認(rèn)知損傷動物模型來明確喹硫平是否通過激活5-HT1a受體功來改善認(rèn)知功能,并選擇觀察PKA活性變化來探討喹硫平通過何種機(jī)制作用于5-HT1a受體來改善認(rèn)知功能。方法：50只青春期雄性大鼠隨機(jī)分成5組(n=10)：對照組、MK-801組、喹硫平組、坦度螺酮加喹硫平組和WAY100635加喹硫平組。對照組接受生理鹽水(1ml/kg i.pqd)14天,其余的大鼠接受MK-801(0.2mg/kg i.pqd)14天。造模結(jié)束24小時后,對照組和MK-801組大鼠蒸餾水灌胃(1ml/Kg i.g qd),其余三組分別接受喹硫平(25mg/kg i.gqd)、喹硫平(25mg/kgi.gqd)和坦度螺酮(0.6mg/kgi.gqd)、喹硫平(25mg/kgi.gqd)和WAY100635(0.1mg/kg i.g qd)給藥10天。之后利用水迷宮試驗測量大鼠空間記憶能力和游泳速度,通過PKA檢測試劑盒檢測海馬細(xì)胞內(nèi)的PKA活性。 結(jié)果：喹硫平組和坦度螺酮加喹硫平組大鼠認(rèn)知功能顯著高于MK-801組。WAY100635加喹硫平組大鼠的認(rèn)知功能顯著低于喹硫平組,而與MK-801組大鼠相比無顯著差異。而坦度螺酮加喹硫平組大鼠的認(rèn)知功能與喹硫平組的大鼠無明顯差異。海馬細(xì)胞內(nèi)的PKA活性分析結(jié)果顯示,喹硫平組和坦度螺酮加喹硫平組顯著高于對照組和MK-801組。坦度螺酮加喹硫平組顯著高于喹硫平組。WAY100635加喹硫平組則顯著低于喹硫平組。 結(jié)論：激活5-HT1a突觸前受體后增強海馬細(xì)胞PKA活性是喹硫平改善MK-801導(dǎo)致的青春期大鼠的認(rèn)知功能損傷的重要機(jī)制之一。這些發(fā)現(xiàn)為研發(fā)更有效的精神分裂癥認(rèn)知障礙治療藥物和方法提供了新思路。
[Abstract]:Part one
Effects of MK-801 on cognitive function and synapse of hippocampal neurons in pubertal rats
Background: cognitive impairment is one of the core symptoms of schizophrenia. The study found that synaptic growth defects are associated with cognitive impairment. Autopsy studies have also found that the hippocampal neurons in the schizophrenic patients also have synaptic growth defect.NMDA receptors in the critical period of adolescent brain development through regulating synaptic pruning and stabilizing the brain. Non competitive NMDA receptor blockers are often used to produce animal models of cognitive impairment in schizophrenia.
Objective: To explore whether the blocking of NMDA receptors in the puberty period can lead to synaptic growth defects in the hippocampal neurons and eventually lead to cognitive impairment. Methods: male puberty rats received 14 days of MK-801 (0.2mg/kg i.p QD) or equal volume of physiological saline intraperitoneal injection to observe their spatial memory ability and the morphological changes of dendritic spines. The expression levels of presynaptic and postsynaptic markers (SYP and PSD-95) and the expression levels of RhoA, Rac1 and Cdc42 genes of synaptogenesis related factors were also changed.
Results: we found that subchronic MK-801 caused cognitive impairment in puberty rats and the diameter of dendritic spines in hippocampal neurons reduced. At the same time, subchronic MK-801 decreased the protein expression of synaptophysin and PSD-95 in the hippocampus neurons of puberty rats. The level of RhoA mRNA expression rose but the mRNA level of Rac1 and Cdc42 was obviously lower. Drop.
Conclusion: the study of synaptic growth defects in the hippocampal neurons by blocking NMDA receptors in the puberty period provides a new direction for exploring the pathogenesis of cognitive impairment of schizophrenia.
The second part
Effects of olanzapine, risperidone and quetiapine on cognitive and hippocampal parvalbumin positive interneurons in MK-801 schizophrenia rats
Background: cognitive impairment is one of the core symptoms of schizophrenia. Non classical antipsychotic drugs can be used to treat cognitive impairment. However, the mechanisms of non classic anti psychotic drugs (APDs) to improve cognitive impairment are still unknown. Autopsy and association studies have proved that synaptic inhibition dysfunction in PV intermediate neurons and cognition of schizophrenic patients The disorders are closely related. Subchronic MK-801 can induce neuropathological changes in adolescent rats similar to the symptoms of cognitive impairment in schizophrenia and the decrease in the number of PV intermediate neurons.
Objective: to select three APDs, the commonly used olanzapine, risperidone and quetiapine, to simulate the MK-801 model of schizophrenic cognitive impairment rats, and to observe the spatial memory cognitive function of the rats and the changes in the density of the intermediate neurons of the hippocampal small albumin.
Methods: 40 male male rats were randomly divided into 5 groups (n=8): control group, MK-801 group, olanzapine group, risperidone group and quetiapine group. The control group received physiological saline (1ml/kg i.p QD) for 14 days, and the rest rats received MK-801 (0.2mg/kg i.p QD) for 14 days. The control group and MK-801 group rats were filled with distilled water after 24 hours (1ml/Kgi.g QD). The remaining three groups were treated with olanzapine (2.5mg/kg Ig QD) and risperidone (1mg/kg Ig QD) quetiapine (25mg/kg Ig QD) for 10 days. Then the water maze test was used to measure the spatial memory ability and swimming speed of rats. The density of hippocampal PV positive cells was detected by immunohistochemical method.
Results: the results showed that MK-801 caused the impairment of cognitive function in puberty rats and the decrease in the number of PV intermediate neurons in the hippocampus of the brain. Risperidone and quetiapine could alleviate the cognitive impairment in spatial memory caused by MK-801 and the decrease of PV intermediate neurons in the hippocampus.
Conclusion: protection of hippocampal PV interneurons may be an important mechanism for non classical APDs to improve cognitive impairment in patients with schizophrenia.
The third part
Quetiapine improves MK-801 induced cognitive impairment by activating 5-HT1a presynaptic receptor
Background: treatment of cognitive impairment has now become the focus of clinical therapy in the psychiatric department. Nonclassical APDs can be used to treat cognitive impairment. However, the mechanism of non classic APDs to improve cognitive impairment is unknown. Autopsy studies have found that the density of 5-HT1a receptors in the brain of schizophrenic patients is rising, which indicates that the function of 5HT1a receptors is abnormal. The study of the 5-HTla receptor in the field of the neurology is mostly focused on emotional disorders. The association of 5-HT1a receptors with cognitive functions has attracted more and more attention in recent years. Non classical APDs is likely to improve cognition by affecting the function of 5-HT1a receptor. Quinolapine is a partial irritable agent of 5-HT.1a receptor, which is excellent for cognitive impairment of schizophrenia. In addition, PKA is one of the most important signal factors in the most classic signal transduction pathway cAMP-PKA pathway mediated by 5-HT1a receptor, which plays an important regulatory role in cognitive function, which leads to the increase of PKA activity when the.5-HT1a presynaptic receptor is activated, and the PKA activity decreases when 5-HT1a postsynaptic receptors are activated.
Objective: to make use of the animal model of cognitive impairment of schizophrenia to determine whether quetiapine can improve cognitive function by activating 5-HT1a receptor work, and to observe the changes in PKA activity to explore the mechanism of quetiapine to improve the cognitive function through the mechanism of 5-HT1a receptor. Methods: 50 young spring male rats were randomly divided into 5 groups (n=10): Group MK-801, quetiapine group, tedipine plus quetiapine group and WAY100635 plus quetiapine group. The control group received physiological saline (1ml/kg i.pqd) for 14 days, the rest of the rats received MK-801 (0.2mg/kg i.pqd) for 14 days. After the end of the model 24 hours, the control group and MK-801 group rats were distilled water (1ml/Kg i.g QD), and the other three groups were treated with quetiapine (25). Mg/kg i.gqd), quetiapine (25mg/kgi.gqd) and stapone (0.6mg/kgi.gqd), quetiapine (25mg/kgi.gqd) and WAY100635 (0.1mg/kg i.g QD) were administered for 10 days. Then the spatial memory ability and swimming speed of rats were measured by water maze test, and PKA activity in hippocampal cells was detected by PKA detection kit.
Results: the cognitive function of the rats in the quetiapine group and the quetiapine group was significantly higher than that in the group MK-801.WAY100635 and quetiapine group, and the cognitive function of the rats in the quetiapine group was significantly lower than that in the quetiapine group, but there was no significant difference compared with that of the MK-801 group. The analysis of PKA activity in horse cells showed that the quetiapine group and the ququetapine group were significantly higher than those in the control group and the MK-801 group. The group of the quetiapine and the quetiapine group was significantly higher than the quetiapine group and the quetiapine group was significantly lower than the quetiapine group, which was significantly lower than that in the quetiapine group.
Conclusion: the activation of PKA activity in hippocampal cells by activating 5-HT1a presynaptic receptor is one of the important mechanisms of quetiapine to improve cognitive impairment in MK-801 induced puberty rats. These findings provide a new way for developing more effective therapeutic drugs and methods for cognitive impairment of schizophrenia.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R749.3;R-332

【參考文獻(xiàn)】

相關(guān)期刊論文 前6條

1 卞士中;張健;劉偉麗;孫志紅;顧振綸;蔣小崗;;NMDA受體拮抗劑與精神分裂癥動物模型[J];法醫(yī)學(xué)雜志;2009年06期

2 譚西英;甘景梨;高存友;段惠峰;;精神分裂癥患者的認(rèn)知功能損害[J];國際精神病學(xué)雜志;2011年01期

3 陳曉崗,陳遠(yuǎn)光;NMDA受體與分裂癥發(fā)病相關(guān)性的分子學(xué)研究進(jìn)展[J];國外醫(yī)學(xué).精神病學(xué)分冊;1999年01期

4 王強,孫學(xué)禮,黃曉琦;精神分裂癥的谷氨酸功能紊亂假說[J];華西醫(yī)學(xué);2003年02期

5 嚴(yán)和殠;;谷氨酸與精神分裂癥[J];上海精神醫(yī)學(xué);2010年03期

6 張志s，

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