Housing conditions have been described elsewhere. Inbred C57BL/6NCrlj (B6) mice were obtained from Charles River Laboratories (Tokyo, Japan). To the best of our knowledge, this is the first report to show that epigenetic modification of nuclear receptor genes has a key role in the prodromal state of schizophrenia, as mediated by PUFA deficiency during early neurodevelopmental stages. Our results identified the RXR and PPAR nuclear receptor signaling system as an upstream mechanism that leads PUFA deficiency to result in schizophrenia-like phenotypes. After confirming this phenomenon, we strove to identify its underlying signaling cascades.

Therefore, in this study, we sought to determine whether deprivation of the essential fatty acids AA and DHA during early development (gestational and early postnatal) in mice elicits schizophrenia-like phenotypes in the adult offspring. 11, 12Р”В¬onsidering the essential role of PUFA, we hypothesized that the compromised availability of dietary PUFA may affect early neurodevelopment and thereby predispose to the development of schizophrenia. 10 Evidence has begun to suggest links between prenatal DHA deficiency and abnormal neurotransmission and neurocognitive impairments. 9 DHA and AA are key components of membrane phospholipids, contributing to the structural integrity of neurons, glial cells and endothelial cells in the brain, 10 and they also affect neurotransmission, cell survival and neuroinflammation.

1 Among the nutrients, the major polyunsaturated fatty acids (PUFAs) arachidonic acid (AA) (20:4 nРІв‚¬вЂ™6) and docosahexaenoic acid (DHA) (22:6 nРІв‚¬вЂ™3) have a critical role in brain development. 8Р”Вeficiencies of several nutrients including folic acids, essential fatty acids, retinoids, vitamin D and iron have been attributed for the schizophrenia risk resulting from gestational famine. 7 Therefore, the diet of pregnant mothers, especially during early developmental stages, influences epigenetic changes in the fetus, such as DNA methylation, thereby affecting the expression of developmentally regulated genes. 2 In addition, long-lasting epigenetic changes are evident in the offspring of women who experience famine during the first trimester of pregnancy, but are absent in those who either do not experience famine or who experience it at a later gestational period. 5, 6 The DOHaD theory has been found to apply to many syndromes and disorders, including schizophrenia. 3, 4 Thus, the adverse conditions during gestation may have lasting effects on subsequent health or result in adult-onset diseases due to fetal programming, which is commonly referred to as the Developmental Origin of Health and Disease (DOHaD). 1 For example, epidemiological evidence indicates that exposure to famine in early gestation approximately doubles the risk of schizophrenia in offspring, as observed after the Dutch Hunger Winter (1944РІР‚вЂњ1945) 2 and the Great Chinese Famine (1959РІР‚вЂњ1961). These results suggest that PUFA deficiency during the early neurodevelopmental period in mice could model the prodromal state of schizophrenia through changes in the epigenetic regulation of nuclear receptor genes.Р”Р„mong the well-established risk factors for schizophrenia that affect early neurodevelopment, nutritional deficiencies are known to have significant effects. Notably, the expression of these nuclear receptor genes were also downregulated in hair-follicle cells from schizophrenia patients. In addition, the RXR agonist bexarotene upregulated oligodendrocyte- and GABA-related gene expression and suppressed the sensitivity of mice to the hallucinogenic drug. Regulation of these genes was mediated by the nuclear receptor genes Rxr and Ppar, whose promoters were hyper-methylated by the deprivation of dietary AA and DHA. Furthermore, a working-memory task-evoked hyper-neuronal activity in the medial prefrontal cortex was also observed, along with the downregulation of genes in the prefrontal cortex involved in oligodendrocyte integrity and the gamma-aminobutyric acid (GABA)-ergic system. In the PUFA-deprived mouse group, we observed lower motivation and higher sensitivity to a hallucinogenic drug resembling the prodromal symptoms in schizophrenia. Here, we show that gestational and early postnatal dietary deprivation of two PUFAs-arachidonic acid (AA) and docosahexaenoic acid (DHA)-elicited schizophrenia-like phenotypes in mouse offspring at adulthood. Polyunsaturated fatty acids (PUFAs) are dietary components that are crucial for the structural and functional integrity of neural cells, and PUFA deficiency has been shown to be a risk factor for schizophrenia. The risk of schizophrenia is increased in offspring whose mothers experience malnutrition during pregnancy.

Smith and wesson 915 schematics