Effects of the Co-Administration of MK-801 and Clozapine on MiRNA Expression Profiles in Rats

Background: microRNAs (miRNAs) are small, non-coding RNAs, which can silence the expression of various target genes via binding their mRNAs, thus miRNAs serve and regulate a wide range of crucial functions in the body. However, the miRNAs expression profile after the antipsychotics mediation in schizophrenia is largely unknown. Methods: Noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonists like as MK-801 had been shown to provide a useful animal model to investigate these effects of schizophrenia-like symptoms in rodent animals. In this study, the rat hippocampal miRNA expression profiles were examined after the antipsychotic clozapine (CLO) treated the MK-801-pretreated Sprague Dawley rats. The total RNA samples from their hippocampus of three rat groups were sequenced using next generation sequencing (NGS), then processed bioinformatic analysis. Results: Successfully, we identified 8 miRNAs' expressions were significantly different in the MK-801 group comparing the VEH control group. Interestingly, 14 miRNAs were largely changed expression in CLO+MK-80-treated group comparing the MK-801-pretreated group, in which the rno-miR-184 was up-regulated significantly. Subsequently, further analyses suggested these miRNAs could modulate their target genes involving in the regulation of endocytosis, ubiquitin mediated proteolysis and regulation of actin cytoskeleton, which might be involved in the important mechanism of schizophrenia. Conclusion: Our results suggested the altered miRNA expressions might play an important role in the complex pathophysiology of schizophrenia, and subsequently impacted on brain functions. Overall design: In our study, we aimed to: 1) compare miRNA expression profiles between MK-801 and VEH control groups and identify differentially expressed miRNAs in two groups, and 2) investigate the effect of one atypical antipsychotic drug (CLO) on hippocampal miRNA expression after CLO treated plus MK-801 with rats. We hypothesize that some miRNAs will be differentially expressed in schizophrenia rats, which will be linked with schizophrenic symptoms.