小柯机器人

美国哈佛医学院波士顿儿童医院Michael C. Carroll课题组宣布他们的最新研究发现过表达精神分裂症易感因子人C4A补体导致小鼠突触过度损伤和行为改变。2020年12月22日，国际学术期刊《自然-神经科学》发表了这一成果。

为了探究补体成分4（C4）A与精神分裂症之间的关系并解决C4A如何在体内重塑大脑回路的问题，研究人员构建了具有灵长类谱系特异性C4、C4A和/或C4B的同工型小鼠模型。人C4A比C4B能更有效的结合突触。C4A而非C4B可以挽救了C4基因敲除小鼠中视觉系统突触细化的缺陷。有趣的是，C4缺乏小鼠的皮层突触数量正常，这表明正常发育的突触不需要补体。

但是，在小鼠中过表达C4A会降低皮质突触密度、增加突触的小胶质细胞吞噬和改变小鼠行为。这些结果表明，C4A过表达介导的突触减少导致了异常的大脑回路和行为。该研究为了解病理性突触过度修饰机制对诸如精神分裂症等疾病的治疗具有重要意义。

据了解，C4与精神分裂症和突触细化相关。在人体中，大脑C4A的高表达与精神分裂症患病风险增加有关。

附：英文原文

Title: Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice

Author: Melis Yilmaz, Esra Yalcin, Jessy Presumey, Ernest Aw, Minghe Ma, Christopher W. Whelan, Beth Stevens, Steven A. McCarroll, Michael C. Carroll

Issue&Volume: 2020-12-22

Abstract: The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia. Overexpression of complement C4A is associated with schizophrenia risk. Using a novel mouse model, Yilmaz et al. find that increased expression of C4A leads to abnormal synaptic pruning and behavior, suggesting its importance as a therapeutic target.

DOI: 10.1038/s41593-020-00763-8

Source: https://www.nature.com/articles/s41593-020-00763-8

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex