Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
Department Woman-Mother-Child, Division of pediatrics, DOHaD Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
Transl Psychiatry. 2023 Feb 1;13(1):30. doi: 10.1038/s41398-023-02322-8.
A large body of evidence suggests that intrauterine growth restriction (IUGR) impedes normal neurodevelopment and predisposes the offspring to cognitive and behavioral deficits later in life. A significantly higher risk rate for schizophrenia (SZ) has been reported in individuals born after IUGR. Oxidative stress and neuroinflammation are both involved in the pathophysiology of SZ, particularly affecting the structural and functional integrity of parvalbumin interneurons (PVI) and their perineuronal nets (PNN). These anomalies have been tightly linked to impaired cognition, as observed in SZ. However, these pathways remain unexplored in models of IUGR. New research has proposed the activation of the MMP9-RAGE pathway to be a cause of persisting damage to PVIs. We hypothesize that IUGR, caused by a maternal protein deficiency during gestation, will induce oxidative stress and neuroinflammation. The activation of these pathways during neurodevelopment may affect the maturation of PVIs and PNNs, leading to long-term consequences in adolescent rats, in analogy to SZ patients. The level of oxidative stress and microglia activation were significantly increased in adolescent IUGR rats at postnatal day (P)35 as compared to control rats. PVI and PNN were decreased in P35 IUGR rats when compared to the control rats. MMP9 protein level and RAGE shedding were also increased, suggesting the involvement of this mechanism in the interaction between oxidative stress and neuroinflammation. We propose that maternal diet is an important factor for proper neurodevelopment of the inhibitory circuitry, and is likely to play a crucial role in determining normal cognition later in life, thus making it a pertinent model for SZ.
大量证据表明，宫内生长受限（IUGR）会阻碍正常的神经发育，并使后代在以后的生活中容易出现认知和行为缺陷。在 IUGR 后出生的个体中，精神分裂症（SZ）的风险率显著增加。氧化应激和神经炎症都参与了 SZ 的病理生理学，特别是影响了 parvalbumin 中间神经元（PVI）及其周围神经网（PNN）的结构和功能完整性。这些异常与 SZ 中观察到的认知障碍密切相关。然而，这些途径在 IUGR 模型中仍未得到探索。新的研究提出 MMP9-RAGE 途径的激活是导致 PVI 持续损伤的原因。我们假设，由于妊娠期间母体蛋白质缺乏引起的 IUGR，会引起氧化应激和神经炎症。这些途径在神经发育过程中的激活可能会影响 PVI 和 PNN 的成熟，导致青春期大鼠出现长期后果，与 SZ 患者类似。与对照组相比，青春期 IUGR 大鼠在出生后第 35 天（P）时，氧化应激和小胶质细胞激活的水平显著增加。与对照组相比，P35 IUGR 大鼠的 PVI 和 PNN 减少。MMP9 蛋白水平和 RAGE 脱落也增加，表明这种机制参与了氧化应激和神经炎症之间的相互作用。我们提出，母体饮食是抑制性电路适当神经发育的重要因素，可能在决定以后的正常认知方面发挥关键作用，因此使其成为 SZ 的一个相关模型。
