Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes

Abstract

The risk of schizophrenia is increased in offspring whose mothers experience malnutrition during pregnancy. 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. 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. In the PUFA-deprived mouse group, we observed lower motivation and higher sensitivity to a hallucinogenic drug resembling the prodromal symptoms in schizophrenia. 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. 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. In addition, the RXR agonist bexarotene upregulated oligodendrocyte- and GABA-related gene expression and suppressed the sensitivity of mice to the hallucinogenic drug. Notably, the expression of these nuclear receptor genes were also downregulated in hair-follicle cells from schizophrenia patients. 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.

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

“…The significant overlap between the yellow expression and the yellow methylation modules mainly involves genes with functions in some metabolic processes, biosynthetic process and fatty acid oxidation, which demonstrated the potential relationship with nervous system development in previous studies [61, 70]. In particular, CpGs nearby genes SLC1A2, SLC1A3 and PRKCA from glutamate synapse showed hypo-methylation in SCZ which may lead to up-regulated expressions of these genes in astrocyte of SCZ, consistent with our results as shown in Table.S1 (Supplementary file 1).…”

The PPARα agonist fenofibrate attenuates disruption of dopamine function in a maternal immune activation rat model of schizophrenia

“…8 Moreover, studies on the ontogeny of MIA-induced deficits showed that these are evident at PND 70. 19,20 Ex vivo electrophysiological experiments were carried out before weaning (PND [12][13][14][15][16][17][18][19][20] to the aim of detect early abnormalities in dopamine neuron activity and synaptic properties.…”

“…Growing evidence suggests that gene expression modulated by PPARα might mitigate the inflammatory component that occurs in psychiatric diseases, such as depression and schizophrenia . Additionally, an association with the gene encoding for PPARα ( PPARA ) was found in patients with schizophrenia and the expression of these nuclear receptor genes was also downregulated in hair‐follicle cells from schizophrenia patients …”

“…15 Additionally, an association with the gene encoding for PPARα (PPARA) was found in patients with schizophrenia 16 and the expression of these nuclear receptor genes was also downregulated in hair-follicle cells from schizophrenia patients. 17 On these bases, the first aim of our study was to investigate the impact of MIA on schizophrenia-related behavior and dopamine transmission in rat female offspring versus males both at preweaning age and during young adulthood. In order to test the hypothesis of sex differences in the outcome of MIA, we designed this investigation as a follow-up of our previous study, whereby, consistent with previous literature, we found that male offspring from Poly I:C-treated dams show marked deficits in prepulse inhibition of startle reflex (PPI) and in dopamine transmission, such as higher baseline levels of dopamine in the nucleus accumbens (NAc) and reduced number and firing rate of spontaneously active VTA dopamine neurons.…”

Proceedings of the 5th annual symposium of the German Society for Paleo Nutrition held in 2017

“…Thus, prenatal experience and maternal Fads2 status have a pervasive, long-lasting influence on the brain development of the offspring [62]. Other 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 [63]. In conclusion, there is a growing body of evidence that omega-3 FA play an important role as well in the first as in the second evolution of man.…”