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.

针对胎儿神经元蛋白的母体抗体的妊娠转移可能与某些神经发育障碍有关，但直到最近还没有发现任何蛋白质。我们最近报道了患有智力和运动障碍儿童的母亲的妊娠中期血清中 CASPR2 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 CASPR2 抗体 (CASPR2-IgGs) 的患者或来自健康对照 (HC-IgGs) 的纯化 IgG。CASPR2-IgG 而不是 HC-IgG 与胎儿脑实质结合，CASPR2-抗体可以从中洗脱。CASPR2-IgG 暴露的新生儿达到了与 HC-IgG 暴露的对照组相似的里程碑，但是，当成年时，CASPR2-IgG 暴露的后代表现出明显的社会交往缺陷，体感皮层 V-VI 层中异常定位的谷氨酸能神经元，激活的小胶质细胞增加 16%，前额叶和体感皮质层中的谷氨酸能突触减少 15-52%。因此，在子宫内暴露于 CASPR2 抗体会导致永久性行为、细胞和突触异常。这些发现支持母体抗体在人类神经发育条件下的致病作用，以及 CASPR2 作为潜在靶标。