Liu Wenhui, Yan Kai, Xu Siqi, Li Lifang, Zhong Mengdan, Liu Jing, Li Guoying, Yang Junhua
Department of Anatomy, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China.
School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Brain Behav Immun. 2025 Feb;124:409-430. doi: 10.1016/j.bbi.2024.12.018. Epub 2024 Dec 15.
Prenatal virus infection-induced maternal immune activation (MIA) is linked to a greater risk of neurodevelopmental disorders in offspring. Prenatal exposure to poly(I:C) in pregnant mice is a well-established approach to mimic virus infection-induced MIA, leading to neuropsychiatric disorders and aberrant brain development, especially in the medial prefrontal cortex (mPFC). ATPase phospholipid flippase 8A2 (ATP8A2) is the main phospholipid lipase, expressed in the mPFC and is crucial for maintaining cell membrane stability by flipping phosphatidylserine from the outer leaflet to the inner leaflet of the cell membrane. Atp8a2 knockout or mutation causes a series of phenotypes, including impaired neuronal cell survival, neuroinflammation, altered synaptic plasticity, and behavioral abnormalities. These findings suggest that ATP8A2 expression in the mPFC may be impaired in MIA offspring and that the decrease in ATP8A2 expression may be involved in the development of MIA-induced neuropsychiatric disorders in offspring. No reports addressing this issue have been published. Here, after confirming abnormal affective-/social-related behaviors in adulthood and reduced synapse-associated protein expression on the birth day (P0) and the fourth postnatal day (P4) in the mPFC of MIA offspring that were born to dams exposed prenatally to a single dose of poly(I:C) (10 mg/kg, i.p.), decreased ATP8A2 expression was also observed in the mPFC of MIA offspring at P0 and P4.Upregulating ATP8A2 in the mPFC restored synapse-associated protein levels, along with a partial improvement in the behavioral performance of MIA offspring. Upregulation of ATP8A2 also blocked neuronal phosphatidylserine externalization and eliminated the excitation/inhibition (E/I) imbalance in the mPFC of MIA offspring. This study revealed that the low expression of ATP8A2 following MIA exposure may play a role in mediating abnormal brain development and function in offspring. ATP8A2 potentially represents a novel molecule involved in MIA-induced neuropsychiatric disorders in offspring, and may serve as a novel therapeutic target for the intervention of psychiatric disorders.
产前病毒感染诱导的母体免疫激活（MIA）与后代神经发育障碍风险增加有关。在怀孕小鼠中产前暴露于聚肌苷酸胞苷酸（poly(I:C)）是一种成熟的模拟病毒感染诱导MIA的方法，会导致神经精神障碍和大脑发育异常，尤其是在内侧前额叶皮质（mPFC）。ATP酶磷脂翻转酶8A2（ATP8A2）是主要的磷脂酶，在mPFC中表达，通过将磷脂酰丝氨酸从细胞膜外小叶翻转到内小叶对维持细胞膜稳定性至关重要。Atp8a2基因敲除或突变会导致一系列表型，包括神经元细胞存活受损、神经炎症、突触可塑性改变和行为异常。这些发现表明，MIA后代的mPFC中ATP8A2表达可能受损，且ATP8A2表达降低可能与MIA诱导的后代神经精神障碍的发生有关。尚未有关于此问题的报道发表。在此，在确认产前暴露于单剂量聚肌苷酸胞苷酸（10 mg/kg，腹腔注射）的母鼠所生MIA后代成年后出现异常的情感/社交相关行为，以及在出生日（P0）和出生后第四天（P4）mPFC中突触相关蛋白表达减少后，在P0和P4的MIA后代的mPFC中也观察到ATP8A2表达降低。在mPFC中上调ATP8A2可恢复突触相关蛋白水平，同时MIA后代的行为表现也有部分改善。ATP8A2的上调还可阻止神经元磷脂酰丝氨酸外化，并消除MIA后代mPFC中的兴奋/抑制（E/I）失衡。本研究表明，MIA暴露后ATP8A2的低表达可能在介导后代大脑发育和功能异常中起作用。ATP8A2可能是参与MIA诱导的后代神经精神障碍的一种新分子，并可能作为精神障碍干预的新治疗靶点。
