RRC ID 49349
著者 Maekawa M, Watanabe A, Iwayama Y, Kimura T, Hamazaki K, Balan S, Ohba H, Hisano Y, Nozaki Y, Ohnishi T, Toyoshima M, Shimamoto C, Iwamoto K, Bundo M, Osumi N, Takahashi E, Takashima A, Yoshikawa T.
タイトル Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes.
ジャーナル Transl Psychiatry
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.
巻・号 7(9)
ページ e1229
公開日 2017-9-5
DOI 10.1038/tp.2017.182
PII tp2017182
PMID 28872641
PMC PMC5639238
MeSH Animals Animals, Newborn Arachidonic Acid / deficiency* Behavior, Animal Cognitive Dysfunction* / etiology Cognitive Dysfunction* / genetics Cognitive Dysfunction* / physiopathology Disease Models, Animal Docosahexaenoic Acids / deficiency* Epigenesis, Genetic / genetics* Female Malnutrition / complications* Mice Mice, Inbred C57BL Milk, Human / chemistry* Prefrontal Cortex* / metabolism Prefrontal Cortex* / physiopathology Pregnancy Pregnancy Complications / metabolism* Prenatal Exposure Delayed Effects* / etiology Prenatal Exposure Delayed Effects* / metabolism Prenatal Exposure Delayed Effects* / physiopathology Prodromal Symptoms Receptors, Cytoplasmic and Nuclear / genetics* Schizophrenia* / etiology Schizophrenia* / genetics Schizophrenia* / physiopathology
IF 5.28
引用数 18
リソース情報
ヒト・動物細胞 OLP6(RCB2864)