星形胶质细胞在免疫刺激诱发的幼年小鼠癫痫发作易感中的作用及机制

发布时间：2018-06-19 22:06

本文选题：星形胶质细胞 + 突触发生　；参考：《浙江大学》2016年博士论文

【摘要】：早期发育阶段癫痫发作的高发性表明发作与癫痫的发生可能与大脑发育密切相关。发育过程中很多危险因素,如免疫刺激,可以影响大脑的发育,提示免疫激活可能是导致大脑发育异常继而引发癫痫的一个关键因素。星形胶质细胞参与调节神经元及其环路的发育过程,其异常发育和功能可诱发包括癫痫在内的许多神经系统发育障碍疾病。此外,模式识别受体Toll样受体4(TLR4)在星形胶质细胞中表达,而TLR4激活与癫痫的发生密切相关。但是在发育过程中星形胶质细胞TLR4激活是否通过调控神经元与突触的发育而造成癫痫发作的易感性这一过程及其机制尚不清楚。在此项研究中,我们发现TLR4配体脂多糖(lipopolysaccharide,LPS)通过激活星形胶质细胞免疫反应,促进发育关键期(出生后第2周)幼年小鼠海马神经元兴奋性突触的发生,从而增加小鼠的癫痫发作易感性。星形胶质细胞TLR4激活通过髓样分化因子88(myeloid differentiation primaryresponseprotein88,MyD88)-依赖性途径上调星形胶质细胞ERK1/2以及phospho-ERK1/2的水平。组成性上调星形胶质细胞ERK1/2的表达可以在不激活TLR4的情况下促进海马神经元上兴奋性突触的发生。特异性敲除星形胶质细胞MyD88或者抑制星形胶质细胞ERK1/2则可以挽救LPS引起的海马神经元兴奋性突触发育异常,并使小鼠的癫痫发作易感性恢复正常。综上所述,我们的研究发现1)发育关键期激活星形胶质细胞可以增加小鼠的癫痫发作易感性;2)星形胶质细胞TLR4-MyD88-ERK信号通路和海马神经元兴奋性突触发生相关;3)激活星形胶质细胞的ERK足以促进海马神经元兴奋性突触发生;4)抑制星形胶质细胞TLR4通路可以使免疫刺激造成的癫痫发作易感现象恢复。
[Abstract]:The high incidence of early developmental seizures suggests that seizures and epilepsy may be closely related to brain development. Many risk factors during development, such as immune stimulation, can affect the development of the brain, suggesting that immune activation may be a key factor leading to abnormal brain development and epilepsy. Astrocytes are involved in regulating the development of neurons and their loops, and their abnormal development and function can induce many neurodevelopmental disorders, including epilepsy. In addition, the pattern recognition receptor Toll-like receptor 4 (TLR4) is expressed in astrocytes, and TLR4 activation is closely related to the occurrence of epilepsy. However, it is not clear whether the activation of TLR4 in astrocytes leads to the susceptibility to epilepsy by regulating the development of neurons and synapses during the development of astrocytes and its mechanism. In this study, we found that TLR4 ligand lipopolysaccharide stimulated excitatory synapses in hippocampal neurons of juvenile mice during the critical developmental period (2 weeks after birth) by activating the astrocyte immune response. So as to increase the susceptibility to epilepsy in mice. The activation of astrocyte TLR4 upregulated the levels of ERK1 / 2 and phospho-ERK1 / 2 in astrocytes through myeloid differentiation factor 88(myeloid differentiation primary responseprotein 88 (MyD88) -dependent pathway. Constitutive up-regulation of ERK1 / 2 expression in astrocytes can promote excitatory synapse formation in hippocampal neurons without activating TLR4. Specifically knockout of astrocyte MyD88 or inhibition of astrocyte ERK1 / 2 could save the excitatory synaptic dysplasia induced by LPS in hippocampal neurons and restore the susceptibility to epilepsy in mice. In summary, Our study found that 1) activation of astrocytes at critical developmental stages increased susceptibility to epilepsy in mice (2) astrocyte TLR4-MyD88-ERK signaling pathway and excitatory synaptophysiogenesis associated with hippocampal neurons activated astrocytes 3) ERK can promote excitatory synaptopenogenesis of hippocampal neurons. Inhibition of astrocyte TLR4 pathway can restore susceptibility to epilepsy induced by immune stimulation.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R741

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