Abstract：
BACKGROUND: Maternal immune activation (MIA) triggers neurobiological changes in offspring, potentially reshaping the molecular synaptic landscape, with the hippocampus being particularly vulnerable. However, critical details regarding developmental timing of these changes and whether they differ between males and females remain unclear.
METHODS: We induced MIA in C57BL/6J mice on gestational day nine using the viral mimetic poly(I:C) and performed mass spectrometry-based proteomic analyses on hippocampal synaptoneurosomes of embryonic (E18) and adult (20 ± 1 weeks) MIA offspring.
RESULTS: In the embryonic synaptoneurosomes, MIA led to lipid, polysaccharide, and glycoprotein metabolism pathway disruptions. In the adult synaptic proteome, we observed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, including cell death and growth, and cytoskeletal organisation. In adults, many associated pathways overlapped between males and females. However, we found distinct sex-specific enrichment of dopaminergic and glutamatergic pathways. We identified 50 proteins altered by MIA in both embryonic and adult samples (28 with the same directionality), mainly involved in presynaptic structure and synaptic vesicle function. We probed human phenome-wide association study data in the cognitive and psychiatric domains, and 49 of the 50 genes encoding these proteins were significantly associated with the investigated phenotypes.
CONCLUSIONS: Our data emphasise the dynamic effects of viral-like MIA on developing and mature hippocampi and provide novel targets for study following prenatal immune challenges. The 22 proteins that changed directionality from the embryonic to adult hippocampus, suggestive of compensatory over-adaptions, are particularly attractive for future investigations.
METHODS: We induced MIA in C57BL/6J mice on gestational day nine using the viral mimetic poly(I:C) and performed mass spectrometry-based proteomic analyses on hippocampal synaptoneurosomes of embryonic (E18) and adult (20 ± 1 weeks) MIA offspring.
RESULTS: In the embryonic synaptoneurosomes, MIA led to lipid, polysaccharide, and glycoprotein metabolism pathway disruptions. In the adult synaptic proteome, we observed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, including cell death and growth, and cytoskeletal organisation. In adults, many associated pathways overlapped between males and females. However, we found distinct sex-specific enrichment of dopaminergic and glutamatergic pathways. We identified 50 proteins altered by MIA in both embryonic and adult samples (28 with the same directionality), mainly involved in presynaptic structure and synaptic vesicle function. We probed human phenome-wide association study data in the cognitive and psychiatric domains, and 49 of the 50 genes encoding these proteins were significantly associated with the investigated phenotypes.
CONCLUSIONS: Our data emphasise the dynamic effects of viral-like MIA on developing and mature hippocampi and provide novel targets for study following prenatal immune challenges. The 22 proteins that changed directionality from the embryonic to adult hippocampus, suggestive of compensatory over-adaptions, are particularly attractive for future investigations.
摘要：
背景：母体免疫激活（MIA）触发后代的神经生物学变化，可能重塑分子突触景观，海马体特别脆弱。然而,关于这些变化的发展时间以及它们在男性和女性之间是否不同的关键细节仍不清楚。
方法：我们在C57BL/6J小鼠妊娠第9天使用病毒模拟poly（I：C）诱导MIA，并对胚胎（E18）和成年（20±1周）MIA后代的海马突触神经体进行基于质谱的蛋白质组学分析。
结果：在胚胎突触神经小体中，MIA导致脂质，多糖，和糖蛋白代谢途径中断。在成年突触蛋白质组中，我们观察到跨膜贩运的动态转变，细胞内信号级联，包括细胞死亡和生长，和细胞骨架组织。在成年人中,许多相关的途径在男性和女性之间重叠。然而,我们发现多巴胺能和谷氨酸能途径的不同性别特异性富集。我们在胚胎和成人样本中鉴定出50种MIA改变的蛋白质（28种具有相同的方向性），主要参与突触前结构和突触小泡功能。我们调查了认知和精神病学领域的人类全表型关联研究数据，50个编码这些蛋白质的基因中有49个与所研究的表型显着相关。
结论：我们的数据强调了病毒样MIA对发育和成熟海马的动态影响，并为产前免疫挑战后的研究提供了新的靶标。从胚胎到成年海马改变方向性的22种蛋白质，暗示补偿性过度适应，对未来的调查特别有吸引力。
方法：我们在C57BL/6J小鼠妊娠第9天使用病毒模拟poly（I：C）诱导MIA，并对胚胎（E18）和成年（20±1周）MIA后代的海马突触神经体进行基于质谱的蛋白质组学分析。
结果：在胚胎突触神经小体中，MIA导致脂质，多糖，和糖蛋白代谢途径中断。在成年突触蛋白质组中，我们观察到跨膜贩运的动态转变，细胞内信号级联，包括细胞死亡和生长，和细胞骨架组织。在成年人中,许多相关的途径在男性和女性之间重叠。然而,我们发现多巴胺能和谷氨酸能途径的不同性别特异性富集。我们在胚胎和成人样本中鉴定出50种MIA改变的蛋白质（28种具有相同的方向性），主要参与突触前结构和突触小泡功能。我们调查了认知和精神病学领域的人类全表型关联研究数据，50个编码这些蛋白质的基因中有49个与所研究的表型显着相关。
结论：我们的数据强调了病毒样MIA对发育和成熟海马的动态影响，并为产前免疫挑战后的研究提供了新的靶标。从胚胎到成年海马改变方向性的22种蛋白质，暗示补偿性过度适应，对未来的调查特别有吸引力。
