Farrelly Lorna, Föcking Melanie, Piontkewitz Yael, Dicker Patrick, English Jane, Wynne Kieran, Cannon Mary, Cagney Gerard, Cotter David R
Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
Dev Neurosci. 2015;37(1):43-55. doi: 10.1159/000368305. Epub 2015 Jan 13.
Maternal infection is a risk factor for schizophrenia but the molecular and cellular mechanisms are not fully known. Myelin abnormalities are amongst the most robust neuropathological changes observed in schizophrenia, and preliminary evidence suggests that prenatal inflammation may play a role.
Label-free liquid chromatography-mass spectrometry was performed on the prefrontal cortex (PFC) of adult rat offspring born to dams that were exposed on gestational day 15 to the viral mimic polyinosinic:polycytidylic acid [poly(I:C), 4 mg/kg] or saline and treated with the atypical antipsychotic drug risperidone (0.045 mg/kg) or saline in adolescence. Western blotting was employed to validate protein changes.
Over 1,000 proteins were quantified in the PFC with pathway analyses implicating changes in core metabolic pathways, following prenatal poly(I:C) exposure. Some of these protein changes were absent in the PFC of poly(I:C)-treated offspring that subsequently received risperidone treatment in adolescence. Particularly interesting reductions in the expression of the myelin-related proteins myelin basic protein isoform 3 (MBP1) and rhombex 29 were observed, which were reversed by risperidone treatment. Validation by Western blotting confirmed changes in MBP1 and mitogen-activated kinase 1 (MAPK1). Western blotting was extended to assess the MAPK signalling proteins due to their roles in inflammation, namely phosphorylated MAPK1 and phosphorylated MAPK-activated protein kinase 2. Both were upregulated by poly(I:C) treatment and reversed by risperidone treatment.
Overall, our data suggest that maternal inflammation may contribute to an increased risk for schizophrenia through mechanisms involving metabolic function and myelin formation and that risperidone in adolescence may prevent or reverse such changes.
母亲感染是精神分裂症的一个风险因素，但其分子和细胞机制尚不完全清楚。髓鞘异常是在精神分裂症中观察到的最显著的神经病理变化之一，初步证据表明产前炎症可能起作用。
对妊娠第15天暴露于病毒模拟物聚肌苷酸:聚胞苷酸[聚（I:C），4mg/kg]或生理盐水的母鼠所生成年大鼠后代的前额叶皮质（PFC）进行无标记液相色谱-质谱分析，并在青春期用非典型抗精神病药物利培酮（0.045mg/kg）或生理盐水处理。采用蛋白质印迹法验证蛋白质变化。
在PFC中定量了1000多种蛋白质，通路分析表明产前聚（I:C）暴露后核心代谢通路发生了变化。其中一些蛋白质变化在随后在青春期接受利培酮治疗的聚（I:C）处理后代的PFC中不存在。特别有趣的是，观察到髓鞘相关蛋白髓鞘碱性蛋白异构体3（MBP1）和菱形蛋白29的表达降低，利培酮治疗可使其逆转。蛋白质印迹法验证证实了MBP1和丝裂原活化蛋白激酶1（MAPK1）的变化。由于其在炎症中的作用，蛋白质印迹法扩展到评估MAPK信号蛋白，即磷酸化MAPK1和磷酸化MAPK活化蛋白激酶2。两者均通过聚（I:C）处理上调，并通过利培酮处理逆转。
总体而言，我们的数据表明，母亲炎症可能通过涉及代谢功能和髓鞘形成的机制增加精神分裂症的风险，青春期的利培酮可能预防或逆转这些变化。
