Altered Molecular Composition of a Specific Subset of Prefrontal Cortical Excitatory Synapses in Schizophrenia.

IF 4 2区 医学 Q1 NEUROSCIENCES
Andrea Lorincz, Maria Ashaber, Zoltan Nusser
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Abstract

Abnormal excitatory synaptic transmission in the human prefrontal cortex has been implicated in the pathophysiology of schizophrenia based primarily on genetic evidence. However, changes in synaptic function cannot be predicted from altered gene expressions, but determining the amount, density, and subsynaptic distribution of synaptic proteins is the only reliable indirect readout of function. Detecting proteins in individual synapses of human postmortem tissues has been severely constrained by technical limitations. Here we overcome this limitation by optimizing a high-resolution, quantitative localization method to facilitate antigen recognition at excitatory synapses in postmortem brains of both sexes. Using PSD-95 immunoreactivity as molecular marker of excitatory synapses, we demonstrate the lack of significant differences in synapse density and size in upper cortical layers of control and schizophrenia subjects. The synaptic densities of postsynaptic AMPA and NMDA receptor subunits and presynaptic molecules Bassoon and Munc13-1 are also indistinguishable between control and schizophrenia subjects. The number of Munc13-1 nanoclusters, marking presynaptic neurotransmitter release sites, does not differ either. Excitatory synapses on parvalbumin expressing interneurons contain similar AMPA but significantly lower NMDA receptor densities in schizophrenia compared with control subjects. Our study provides the first comprehensive comparison of key functionally relevant synaptic proteins in individual human excitatory synapses and demonstrates that changes in the molecular composition of only a specific subset of excitatory synapses may contribute to the pathophysiology of schizophrenia.

精神分裂症患者前额皮质兴奋性突触特定亚群的分子组成改变。
基于遗传证据,人类前额叶皮层异常兴奋性突触传递与精神分裂症的病理生理有关。然而,突触功能的变化不能通过基因表达的改变来预测,但确定突触蛋白的数量、密度和亚突触分布是唯一可靠的间接功能读数。在人类死后组织的单个突触中检测蛋白质受到技术限制的严重限制。在这里,我们通过优化一种高分辨率的定量定位方法来克服这一限制,以促进死后两性大脑兴奋性突触中的抗原识别。利用PSD-95免疫反应性作为兴奋性突触的分子标记,我们发现对照组和精神分裂症被试在上皮层突触密度和大小上没有显著差异。精神分裂症被试的突触后AMPA和NMDA受体亚基、突触前分子Bassoon和Munc13-1的突触密度在对照组和精神分裂症被试之间也无显著差异。标记突触前神经递质释放位点的Munc13-1纳米簇的数量也没有差异。表达小白蛋白的中间神经元上的兴奋性突触含有相似的AMPA,但与对照组相比,精神分裂症患者的NMDA受体密度显著降低。我们的研究首次全面比较了人类兴奋性突触中关键功能相关的突触蛋白,并证明了兴奋性突触中特定子集的分子组成的变化可能与精神分裂症的病理生理有关。前额叶皮层异常兴奋性突触传递与精神分裂症的病理生理有关。我们的研究为精神分裂症兴奋性突触功能障碍的分子机制提供了新的见解。利用高分辨率定位方法和改进的抗原识别,我们提供了人类皮层兴奋性突触中关键突触蛋白的密度和亚突触分布的全面分析。虽然我们发现总的突触密度和兴奋性突触的分子组成没有显著差异,但我们的研究结果显示,在精神分裂症受试者中,针对表达小白蛋白的中间神经元的突触中,NMDA受体密度有所降低。这些发现表明,仅皮质突触的一个特定子集的分子组成的变化可能有助于精神分裂症的病理生理。
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来源期刊
Journal of Neuroscience
Journal of Neuroscience 医学-神经科学
CiteScore
9.30
自引率
3.80%
发文量
1164
审稿时长
12 months
期刊介绍: JNeurosci (ISSN 0270-6474) is an official journal of the Society for Neuroscience. It is published weekly by the Society, fifty weeks a year, one volume a year. JNeurosci publishes papers on a broad range of topics of general interest to those working on the nervous system. Authors now have an Open Choice option for their published articles
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