Low protein-induced intrauterine growth restriction as a risk factor for schizophrenia phenotype in a rat model: assessing the role of oxidative stress and neuroinflammation interaction

Abstract

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.

Unraveling the Molecular Mechanisms of the Neurodevelopmental Consequences of Fetal Protein Deficiency: Insights From Rodent Models and Public Health Implications

“…While a wealth of data exist for the neuronal component, our understanding of its impact on other cell types such as oligodendrocytes, astrocytes, and microglia remains limited. To our knowledge, only one study has revealed that gestational protein restriction in rats induces microglia to a state of hyperactivity, elevating oxidative stress and neuroinflammatory markers in adult stages ( 113 ). In addition, exploring the role of the placenta as a fetal caretaker in abnormal nutritional conditions deserves more attention ( 114 , 115 ).…”

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence

“…[50] (×20), [51]; [89] WFA, Aβ (Amylo-Glo), CD68, Iba1, Thioflavin-S, PV, Aggrecan, Crtl1, GAD65/67, vGlut1, Cat-301, calretinin, MAP2, VGAT, brevican Schizophrenia, bipolar disorder [42] (×20/0.5; ×63/1.4); [99]; [100] (×20/0.5); [101] (×20; ×40) WFA, PV, HNK-1, S100-β, CS56, MMP9, 8-oxo-dG, CD68, Iba1 Substance use disorder [102] (×20/0.7; ×63/1.4); [103] (×20/0.75; ×20/0.7); [104] (×40); [105] (×63/1.4); [106] (×40), [107]; [32] (×20/0. Hibernation-like state [113] AI-assisted Normal brain [34,36] WFA, parvalbumin…”

Negative environmental influences on the developing brain mediated by epigenetic modifications

“…Maternal undernutrition leads to intrauterine which several studies have linked with lower IQ scores [89]. A systematic review and meta-analysis of 35 studies involving over 8,000 children found that those born with intrauterine growth restriction (IUGR) had, on average, lower IQ scores than those born with normal birth weights [90]. In addition to lower IQ, IUGR has also been linked to an increased risk of schizophrenia.…”