Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero.
Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero.
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DOI：
10.1007/s00401-017-1751-5
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发表时间：
2017-10
影响因子：
12.7
通讯作者：
Vincent A
中科院分区：
文献类型：
--
作者：
Coutinho E;Menassa DA;Jacobson L;West SJ;Domingos J;Moloney TC;Lang B;Harrison PJ;Bennett DLH;Bannerman D;Vincent A
针对胎儿神经元蛋白的母体抗体的妊娠转移可能与一些神经发育障碍有关，但直到最近还没有鉴定出蛋白质。我们最近报道了智力和运动障碍儿童母亲的妊娠中期血清中CASPR 2抗体增加了五倍。在这里，我们将子宫内的小鼠暴露于来自具有CASPR 2抗体的患者（CASPR 2-IgG）或来自健康对照（HC-IgG）的纯化IgG。CASPR 2-IgG而不是HC-IgG结合到胎脑实质，CASPR 2-抗体可以从胎脑实质洗脱。暴露于CASPR 2-IgG的新生儿实现了与暴露于HC-IgG的对照相似的里程碑，但是当成年时，暴露于CASPR 2-IgG的后代显示出显著的社会互动缺陷、躯体感觉皮层的V-VI层中异常定位的突触能神经元、活化的小胶质细胞增加16%以及前额和躯体感觉皮层层中的突触能突触减少15-52%。因此，在子宫内暴露于CASPR 2抗体导致永久性行为、细胞和突触异常。这些发现支持母体抗体在人类神经发育状况中的致病作用，以及CASPR 2作为潜在靶点。本文的在线版本（doi：10.1007/s 00401 -017-1751-5）包含补充材料，可供授权用户使用。
Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V–VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15–52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target. The online version of this article (doi:10.1007/s00401-017-1751-5) contains supplementary material, which is available to authorized users.
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影响因子：
--
作者：
Palmeira P;Quinello C;Silveira-Lessa AL;Zago CA;Carneiro-Sampaio M
通讯作者：
Carneiro-Sampaio M
DOI：
10.1136/jnnp-2016-315251
发表时间：
2017-09
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Coutinho E;Jacobson L;Pedersen MG;Benros ME;Nørgaard-Pedersen B;Mortensen PB;Harrison PJ;Vincent A
通讯作者：
Vincent A
影响因子：
3
作者：
Martinez-Cerdeno, Veronica
通讯作者：
Martinez-Cerdeno, Veronica
影响因子：
6.8
作者：
Braunschweig D;Krakowiak P;Duncanson P;Boyce R;Hansen RL;Ashwood P;Hertz-Picciotto I;Pessah IN;Van de Water J
通讯作者：
Van de Water J
DOI：
10.1073/pnas.1216398109
发表时间：
2012-10-30
影响因子：
11.1
作者：
Anderson, Garret R.;Galfin, Timothy;Suedhof, Thomas C.
通讯作者：
Suedhof, Thomas C.