本文選題：自閉癥譜系障礙　切入點(diǎn)：GABA_AR內(nèi)吞作用　出處：《重慶醫(yī)科大學(xué)》2017年碩士論文

【摘要】：背景;自閉癥譜系障礙主要表現(xiàn)為:1、社交溝通障礙;2、刻板重復(fù)的行為和興趣狹窄。其發(fā)病機(jī)制長(zhǎng)期困擾著全世界的專家學(xué)者們,同時(shí)由于其發(fā)病機(jī)制尚不明確,使有效的治療措施的發(fā)現(xiàn)變得難上加難。目前,‘興奮抑制失衡’理論被廣泛認(rèn)可和接受,該理論認(rèn)為大腦中異常的興奮/抑制信號(hào)傳導(dǎo)引起了自閉癥患兒的一系列異常行為表現(xiàn)。其中抑制信號(hào)的傳導(dǎo)與GABA_AR關(guān)系十分緊密,所以GABA_AR的異常及其偶聯(lián)的離子共轉(zhuǎn)運(yùn)體NKCC1和KCC2的異常無(wú)疑會(huì)影響抑制性信號(hào)的傳導(dǎo)。同時(shí),自閉癥譜系障礙作為一種發(fā)育性障礙,大多情況下在患兒3歲時(shí)才能被明確診斷,但大量證據(jù)表明其損傷性的病變?cè)谏脑缙陔A段便開(kāi)始了。目的;探討自閉癥模型大鼠中各個(gè)生長(zhǎng)發(fā)育階段GABA_AR的變化情況及行為異常。方法:使用VPA誘導(dǎo)的自閉癥模型大鼠作為實(shí)驗(yàn)組,VPA溶解于生理鹽水。對(duì)照組為僅暴露于生理鹽水的子代大鼠。從出生后0天開(kāi)始對(duì)其生長(zhǎng)發(fā)育情況進(jìn)行測(cè)評(píng),包括平面翻正、空中翻正、負(fù)趨地性、斷崖回避、聽(tīng)覺(jué)驚愕作為其神經(jīng)發(fā)育的指標(biāo),而體重、立耳、牙齒萌出、睜眼情況則反映了其身體發(fā)育情況。出生后35天起,進(jìn)行Morris水迷宮、礦場(chǎng)實(shí)驗(yàn)和三箱實(shí)驗(yàn),檢測(cè)其空間記憶、焦慮狀態(tài)、對(duì)陌生環(huán)境探索的興趣及社交行為。然后運(yùn)用Western blot的方法分別檢測(cè)PD7、PD14、PD28、PD56大鼠4個(gè)腦區(qū)中GABA_ARβ3、m-GABA_ARβ3、p-GABA_ARβ3、KCC2、NKCC1的表達(dá)量。各個(gè)時(shí)間點(diǎn)的腦組織來(lái)源于按隨機(jī)原則從相應(yīng)時(shí)間點(diǎn)的兩組中選取的6只大鼠(模型組和對(duì)照組各3只)。結(jié)果:(1)自閉癥模型大鼠身體發(fā)育情況較對(duì)照組無(wú)名明顯差異,但神經(jīng)發(fā)育情況明顯滯后于對(duì)照組。(2)通過(guò)Morris水迷宮實(shí)驗(yàn),我們發(fā)現(xiàn)自閉癥模型大鼠存在一定的空間記憶障礙和相對(duì)低下的運(yùn)動(dòng)能力;在礦場(chǎng)實(shí)驗(yàn)中,自閉癥大鼠則表現(xiàn)出了明顯的焦慮狀態(tài)和減少的探索性趣;三箱實(shí)驗(yàn)中模型組則有明顯的社交障礙的表現(xiàn)。(3)自閉癥模型大鼠各時(shí)間點(diǎn)各腦區(qū)與對(duì)照組相比,m-GABA_ARβ3、pGABA_ARβ3、KCC2的表達(dá)量均減少,但總的GABA_ARβ3和NKCC1的表達(dá)并無(wú)顯著差異。結(jié)論:(1)自閉癥模型大鼠除表現(xiàn)出核心癥狀社交障礙和探索興趣下降外,還表現(xiàn)出明顯的神經(jīng)發(fā)育遲滯、焦慮狀態(tài)、運(yùn)動(dòng)協(xié)調(diào)能力下降及空間記憶障礙。(2)自閉癥模型大鼠各時(shí)間點(diǎn)各腦區(qū)均有GABA_AR的異常。(3)引起該異常的機(jī)制之一可能是GABA_ARβ3去磷酸化介導(dǎo)的GABA_AR內(nèi)吞作用增加。
[Abstract]:Background: autism spectrum disorders are mainly expressed as: 1, social communication, stereotypical behavior and narrow interests. The pathogenesis of autism spectrum disorders has long plagued experts and scholars all over the world, while the pathogenesis of autism spectrum is still unclear. It makes the discovery of effective treatment even more difficult. Currently, the theory of "excitation-suppression imbalance" is widely accepted and accepted. The theory suggests that abnormal excitatory / inhibitory signal transduction in the brain causes a series of abnormal behaviors in autistic children. The inhibitory signal transduction is closely related to GABA_AR. So the abnormality of GABA_AR and its coupling ion cotransporter NKCC1 and KCC2 will undoubtedly affect the signal transduction of inhibition. Meanwhile, autism spectrum disorder, as a developmental disorder, is usually diagnosed at the age of 3. But there is plenty of evidence that the lesion begins at an early stage of life. To investigate the changes and behavioral abnormalities of GABA_AR in various growth and development stages of autistic rats. Methods: VPA induced autistic model rats were used as experimental groups to dissolve GABA_AR in normal saline, while those in control group were only exposed to physiological conditions. The offspring of saltwater. The growth and development of rats were evaluated from 0 days after birth. Including plane inversion, aerial inversion, negative geodesic, cliff avoidance, auditory consternation as indicators of neurodevelopment, and weight, ear, teeth eruption, and eye opening, which reflect their physical development. 35 days after birth, Morris water maze, field experiment and three-box experiment were carried out to detect their spatial memory and anxiety. The Western blot method was used to detect the expression of GABA_AR 尾 3, m-GABAAR 尾 3, p-GABAAR 尾 3, p-GABAAR 尾 3, KABAAR 尾 3 and KABAAR 尾 3 KCC2NKCC1 in four brain regions of PD7 / PD14 / PD28 / PD56 rats respectively. The brain tissue at each time point was derived from the two groups of corresponding time points according to random principle. Six rats (3 in model group and 3 in control group) were selected. Results the development of autistic rats was significantly different from that of unnamed rats in control group. But the neural development lags behind that of the control group. (2) through the Morris water maze experiment, we found that there are some spatial memory disorders and relatively low motor ability in the autistic model rats. The rats with autism showed obvious anxiety and decreased exploratory interest, while the model group showed obvious social disorder in the three-box experiment.) the expression of m-GABAAR 尾 3pGABAAR 尾 3pGABAAR 尾 3pGABAAR 尾 3KCC2 was decreased in each brain area of the model rats compared with the control group at each time point. But there was no significant difference between the expression of GABA_AR 尾 3 and NKCC1. Conclusion the rat model of autism not only showed the core symptoms of social disorder and decreased interest in exploration, but also showed obvious neurological retardation and anxiety. The decrease of motor coordination ability and spatial memory impairment. 2) there is abnormal GABA_AR in all brain regions of autism model rats at all time points.) one of the mechanisms of this abnormality may be the increase of GABA_AR endocytosis mediated by GABA_AR 尾 3 dephosphorylation.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R749.94;R-332

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 Anne Masi;Nicholas Glozier;Russell Dale;Adam J.Guastella;;The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder[J];Neuroscience Bulletin;2017年02期

，

本文編號(hào)：1675854