发育期海马星形胶质细胞激活对小鼠自闭症样行为的影响及机制研究

发布时间：2018-02-15 12:05

本文关键词： 自闭症谱系障碍星形胶质细胞海马 GABA能神经元发育期　出处：《浙江大学》2017年硕士论文　论文类型：学位论文

【摘要】：自闭症谱系障碍(ASD,Autism Spectrum Disorder)是一类较为严重的发育障碍性疾病,其致病因素极其复杂,很可能是遗传和环境因素在脑发育关键时期共同作用的结果。在大脑的发育阶段,星形胶质细胞可通过调节突触形成、突触功能、突触消除、神经元存活和轴突导向等来"精心策划"神经系统发育。不同发育阶段星形胶质细胞发育和功能的异常可能会导致多种神经发育疾病的发生。研究发现ASD患者脑内存在星形胶质细胞的过度激活,提示星形胶质细胞活性可能与ASD相关。神经环路兴奋和抑制功能失衡很可能是导致ASD的重要病理机制,而星形胶质细胞对于神经元发育和神经环路的平衡至关重要。以上证据提示,在特定发育阶段,星形胶质细胞很可能通过影响神经元发育以及神经环路兴奋性与抑制性的平衡参与ASD。但是具体机制尚不清楚。在此项研究中,我们通过子宫内胚胎电转(胚胎第15天,E15)表皮生长因子受体(epidermal growth factor receptor,EGFR)质粒,成功建立了单侧海马星形胶质细胞激活的小鼠模型。我们发现:1)行为学检测结果显示,与对照质粒组小鼠相比,单侧海马星形胶质细胞激活组小鼠社交行为有明显的降低,理毛行为则显著增加,但是水迷宫和旷场实验结果差异不明显;2)高尔基染色结果显示,与未转染EGFR侧的海马神经元以及对照质粒组小鼠的海马神经元相比,EGFR转染侧(星形胶质细胞激活侧)的神经元树突棘密度明显降低;3)免疫组化结果显示,与未转染EGFR侧海马脑区相比,EGFR转染侧的GAD67阳性神经元数目显著增加,说明GABA能神经元数量增加。以上结果提示,在出生前和出生后早期的发育关键期,海马星形胶质细胞激活可能通过影响神经元兴奋性和抑制性功能的平衡而导致小鼠自闭症样行为。
[Abstract]:Autistic spectrum disorder Spectrum disorderis a kind of serious developmental disorder, and its pathogenic factors are extremely complex, which is probably the result of the combination of genetic and environmental factors during the critical period of brain development. Astrocytes can regulate synapse formation, synaptic function, synaptic elimination, Neuronal survival and axon orientation are "carefully planned" for the development of the nervous system. Abnormalities in astrocyte development and function at different stages of development may lead to multiple neurodevelopmental diseases in the brain of patients with ASD. There is excessive activation of astrocytes, The results suggest that astrocyte activity may be related to ASD. The imbalance of neural loop excitation and inhibition may be an important pathogenetic mechanism of ASD. Astrocytes are critical to the development of neurons and the balance of neural loops. The evidence suggests that at certain stages of development, Astrocytes may be involved in ASD by affecting neuronal development and balancing excitability and inhibition in the neural loop, but the exact mechanism is not clear. We successfully established a mouse model of unilateral hippocampal astrocyte activation using epidermal growth factor receptor epidermal growth factor receptor EGFR plasmid (E15 on day 15 of embryo). Compared with the control plasmid group, the social behavior of unilateral hippocampal astrocyte-activated group was significantly decreased, but the hairdressing behavior was significantly increased, but there was no significant difference between the water maze and open field test results. Compared with the hippocampal neurons in the untransfected EGFR side and the hippocampal neurons in the control group, the density of dendritic spine in the EGFR-transfected side (the activation side of astrocytes) was significantly lower than that in the control group. Compared with the untransfected EGFR side, the number of GAD67 positive neurons in the pEGFR-transfected side was significantly increased, which indicated that the number of GABA neurons increased. The activation of hippocampal astrocytes may result in autistic behavior by affecting the balance of neuronal excitability and inhibitory function.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.94

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