Our previous study has suggested that peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the pathophysiology of schizophrenia. In the current study, we screened and identified rare variants in the PPARA gene (encoding PPARα) of schizophrenia subjects. In vitro study showed that those variants decreased activities of PPARα as a transcription factor. Ppara KO mice exhibited a deficit in the sensorimotor gating function and schizophrenia-related histological abnormalities. RNA-seq analysis revealed that PPARα regulates the expression of synaptogenesis signaling pathway-related genes in the brain. Remarkably, treatment of mice with the PPARα agonist fenofibrate alleviated an NMDA receptor antagonist, phencyclidine (PCP)-induced spine pathology and reduced sensitivity to MK-801, another NMDA receptor antagonist. In conclusion, the current study further supports the idea that perturbation in the PPARα-regulated transcriptional machinery leads to a predisposition to schizophrenia, probably by affecting synapse physiology. This study also demonstrates that PPARα can serve as a novel therapeutic target for schizophrenia.
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