MiR-127 Modulates Acute PCP And MK-801-induced Neurobehavioral Dysfunction

Objective:Phencyclidine(PCP)and dizocilpine(MK-801)are antagonists of N-methyl-D-aspartate(NMDA)glutamate receptor.They were used to induce phychotomimetic activity.Neuregulin 1(NRG1)and its receptors ErbB played an important role in the development of schizophrenia.MiR-127 affected the expression of ErbB4,which was a receptor of schizophrenia risk gene NRG1.Therefore,we investigated the change of miR-127 in acute MK-801 and PCP-induced neurobehavioral dysfunction.Methods:PCP(4 mg/kg s.c.)and MK-801(0.4 mg/kg i.p.)were injected to mice to induce acute neurobehavioral dysfunction.The expression of miR-127 in various brain regions after PCP and MK-801 treatment was detected by Real-time PCR.In vitro,we detected the expression level of miR-127 with NMDA receptor specific antagonist AP-5 treatment in primary cortical neuron by Real-time PCR.We tested that if pretreatment(30 min)with clozapine,an atypical antipsychotic drug,could alter acute MK-801-mediated change in miR-127 expression.To test the functional implication of miR-127 in MK-801-induced hyperlocomotion and prepulse inhibition(PPI),MK-801-induced locomotion activity and PPI were tested after knockdown of miR-127 by stereotaxic injection to the third ventricle.Western blot and luciferase reporter assay were performed to identify the target protein of miR-127.Results:The results showed that miR-127 levels were significantly decreased in prefrontal cortex,hippocampus and striatum in a short of time following PCP or MK-801 administration.In vitro,we found that miR-127 levels were also decreased at 30 min after NMDA receptor specific antagonist AP-5 treatment in primary cortical neuron.Clozapine attenuated MK-801-induced hyperlocomotion in mice,but did not alter MK-801-decreased miR-127 expression,and clozapine alone also decreased miR-127 expression.Knockdown of miR-127 in prefrontal cortex did not affect the acute MK-801-induced decrease of hyperlocomotion and PPI.Western blot and luciferase reporter assay suggested that miR-127 directly target the 3'un-translated region(UTR)of synaptopodin(SYNPO)mRNA to reduce the protein levels of SYNPO in prefrontal cortex,indicating that SYNPO may be the target protein of miR-127Conclusions:These findings suggest that acute MK-801 or PCP induced transit decrease of miR-127 in brain tissues,which is likely mediated by blocking NMDA receptors.The transit change in miR-127 appears to not associated with MK-801-induce hyperlocomotion and PPI.Lastly,we found that miR-127 may play an important role in regulation SYNPO expression.