Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
Ann Neurol. 2019 Nov;86(5):656-670. doi: 10.1002/ana.25552. Epub 2019 Sep 18.
Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy.
We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior.
Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem.
The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.
母体自身抗体是导致后代大脑发育受损的一个风险因素。针对 N-甲基-D-天冬氨酸受体（NMDAR）NR1（GluN1）亚单位的抗体（ABs）是最常被诊断出的抗神经元表面 ABs 之一，但对于其在怀孕期间对胎儿发育的影响知之甚少。
我们建立了一种在子宫内暴露于人类重组 NR1 和同型匹配的非反应性对照 AB 的小鼠模型。妊娠 C57BL/6J 小鼠于胚胎第 13 天和第 17 天，经腹腔内注射 240μg 的人单克隆 AB。研究了后代的 NMDAR 功能、大脑发育和行为的急性和慢性影响。
转染的 NR1 AB 在胎儿中富集，并与胎儿大脑中的突触结构结合。NMDAR 的密度显著降低（高达-49.2%），电生理特性发生改变，表现为幼年新生鼠自发兴奋性突触后电流幅度降低（-34.4%）。NR1 AB 处理的动物表现出早期产后死亡率增加（+27.2%）、神经发育反射受损、血液 pH 值改变和体重减轻。在青春期和成年期，动物表现出多动（14 天内中位数活动增加+27.8%）、焦虑降低和感觉运动门控受损。NR1 AB 还导致老年小鼠（10 个月）出现长期神经病理学效应，如小脑、中脑和脑干体积减少。
这些数据共同支持了一种模型，即无症状的母亲可以携带低水平的致病性人类 NR1 AB，这些 AB 可以通过胎盘转移，对新生儿的发育造成神经毒性影响。因此，AB 介导的网络变化可能代表一种潜在可治疗的神经发育性先天性脑障碍，导致受影响儿童终生神经精神发病率增加。ANN NEUROL 2019；86：656-670。
