Abstract
We have previously reported that dietary deprivation of polyunsaturated fatty acid (PUFA) during neurodevelopmental stages in mice elicited schizophrenia‐like phenotypes in its offspring at adulthood, and that the nuclear receptor peroxisome proliferator‐activated receptor (PPAR) /retinoid X receptor (RXR) system may act as an underlying mechanism linking PUFA deficiency and the behavioral phenotypes. In this study, we further examined whether the PPAR/RXR system is associated with the pathophysiology of schizophrenia. Firstly, we screened for mutations in all the PPAR/RXR genes using the samples of 1,200 Japanese patients with schizophrenia. Based on in silico analyses, we focused on the PPARA gene and its variants (c.209‐2delA, His117Gln, Arg141Cys, and Arg226Trp) that were found exclusively in schizophrenia, but not in control population. The c.209‐2delA variant caused skipping of exon 4, generating a premature termination codon. All the three missense variants decreased the activity of PPARα as a transcription factor in vitro. Next, we examined a Ppara KO mouse model to evaluate the biological consequences evoked by a functional deficiency of this gene in vivo. The Ppara KO mice exhibited behavioral and histological phenotypes that are reminicent of schizophrenia. In conclusion, these findings reinforce the idea that PPARα can be involved in the pathophysiology of schizophrenia.
