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亨廷顿病小鼠模型中丘脑和皮质到纹状体棘状投射神经元的兴奋性突触的差异变化。

Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model.

作者信息

Kolodziejczyk Karolina, Raymond Lynn A

机构信息

Department of Psychiatry, Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Psychiatry, Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

出版信息

Neurobiol Dis. 2016 Feb;86:62-74. doi: 10.1016/j.nbd.2015.11.020. Epub 2015 Nov 24.

Abstract

Huntington disease (HD), a neurodegenerative disorder caused by CAG repeat expansion in the gene encoding huntingtin, predominantly affects the striatum, especially the spiny projection neurons (SPN). The striatum receives excitatory input from cortex and thalamus, and the role of the former has been well-studied in HD. Here, we report that mutated huntingtin alters function of thalamostriatal connections. We used a novel thalamostriatal (T-S) coculture and an established corticostriatal (C-S) coculture, generated from YAC128 HD and WT (FVB/NJ background strain) mice, to investigate excitatory neurotransmission onto striatal SPN. SPN in T-S coculture from WT mice showed similar mini-excitatory postsynaptic current (mEPSC) frequency and amplitude as in C-S coculture; however, both the frequency and amplitude were significantly reduced in YAC128 T-S coculture. Further investigation in T-S coculture showed similar excitatory synapse density in WT and YAC128 SPN dendrites by immunostaining, suggesting changes in total dendritic length or probability of release as possible explanations for mEPSC frequency changes. Synaptic N-methyl-D-aspartate receptor (NMDAR) current was similar, but extrasynaptic current, associated with cell death signaling, was enhanced in YAC128 SPN in T-S coculture. Employing optical stimulation of cortical versus thalamic afferents and recording from striatal SPN in brain slice, we found increased glutamate release probability and reduced AMPAR/NMDAR current ratios in thalamostriatal synapses, most prominently in YAC128. Enhanced extrasynaptic NMDAR current in YAC128 SPN was apparent with both cortical and thalamic stimulation. We conclude that thalamic afferents to the striatum are affected early, prior to an overt HD phenotype; however, changes in NMDAR localization in SPN are independent of the source of glutamatergic input.

摘要

亨廷顿舞蹈症(HD)是一种由编码亨廷顿蛋白的基因中CAG重复序列扩增引起的神经退行性疾病,主要影响纹状体,尤其是棘状投射神经元(SPN)。纹状体接收来自皮层和丘脑的兴奋性输入,前者在HD中的作用已得到充分研究。在此,我们报告突变的亨廷顿蛋白会改变丘脑 - 纹状体连接的功能。我们使用了一种新型的丘脑 - 纹状体(T - S)共培养体系以及一种已建立的皮质 - 纹状体(C - S)共培养体系,它们分别由YAC128 HD和野生型(FVB/NJ背景品系)小鼠构建而成,以研究对纹状体SPN的兴奋性神经传递。野生型小鼠T - S共培养体系中的SPN显示出与C - S共培养体系中相似的微小兴奋性突触后电流(mEPSC)频率和幅度;然而,YAC128 T - S共培养体系中的频率和幅度均显著降低。在T - S共培养体系中的进一步研究通过免疫染色显示野生型和YAC128 SPN树突中兴奋性突触密度相似,这表明总树突长度的变化或释放概率可能是mEPSC频率变化的原因。突触N - 甲基 - D - 天冬氨酸受体(NMDAR)电流相似,但与细胞死亡信号相关的突触外电流在T - S共培养体系中的YAC128 SPN中增强。利用对皮层与丘脑传入纤维的光学刺激以及在脑片中记录纹状体SPN,我们发现在丘脑 - 纹状体突触中谷氨酸释放概率增加,且AMPA受体/NMDAR电流比值降低,在YAC128中最为明显。在皮层和丘脑刺激下,YAC128 SPN中增强的突触外NMDAR电流均很明显。我们得出结论,在明显的HD表型出现之前,丘脑向纹状体的传入纤维就已早期受到影响;然而,SPN中NMDAR定位的变化与谷氨酸能输入的来源无关。

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