| Background:Autism Spectrum Disorder(ASD)is a kind of common and heterogeneous clinical neurodevelopmental disorder and appears in early childhood.Its main clinical symptoms are sociability absence and repetitive behavior.Maternal high fat diet can lead to maternal obesity and induce neurodevelopmental disorders in offspring by altering maternal uterine environment,and the mechanisms include inflammation and epigenetics.The previous research results of our research group showed that the expression level of miR-125b-5p in neonatal umbilical cord blood of obese parturients significantly changed.miR-125b-5p regulates the expression of neuronal differentiation and synaptic plasticity related genes after transcription and participates in the neurodevelopment.miR-125b-5p may be related to ASD.Objects:To explore maternal high fat diet on ASD related behaviors in offspring mice,and to study miR-125b-5p participating in the mechanism of the experiment.Methods:C57BL/6J female mice were fed with high fat diet(HFD)or standard diet(SD)for 12 weeks.After 12 weeks,some female mice were randomly selected for neurobehavioral tests related to ASD,including three-chamber social test,nest building test,marble burying test,elevated plus-maze test and open field test,which were used to detect sociability,repetitive behavior,anxiety and motor ability.Other female mice mated with C57BL/6J male mice to obtain offspring mice.The female mice in the HFD group maintained high fat diet during pregnancy and lactation.The maternal high fat diet(MHFD)and matenal standard diet(MSD)of offspring mice were fed with standard diet after weaning.The offspring mice were subjected to neurobehavioral tests related to ASD.The expression level of miR-125b-5p in the adipose tissue and prefrontal cortex(PFC)and was detected by RT-q PCR in female mice.The expression level of miR-125b-5p in the PFC of offspring mice at gestational day 14(G14)and postnatal day 1,8 and 28(P1,P8,P28)were detected by RT-q PCR.The plasmid overexpressing miR-125b-5p was constructed to transfect the mouse neuroblastoma N2 a cells,the expression of candidate target genes at protein levels in N2 a cells after transfection and in the PFC of MSD/MHFD offspring mice at postnatal day 28 were detected by western blot(WB).Results:1.After 12 weeks of feeding,the average weight of female mice fed with HFD was about30% higher than that of SD-fed female mice.2.The HFD-fed females did not show autism-related behaviors: normal sociability,no repetitive behavior,no anxiety behavior,and normal motor abilitity.3.The MHFD offspring mice showed autism-related behaviors: sociability absence,repetitive behavior,anxiety and motor impairment;these behaviors were not caused by maternal heredity.4.The expression level of miR-125b-5p was up-regulated in the adipose tissue of HFDfed female mice,and was not significantly changed in the PFC.The expression level of miR-125b-5p in the PFC of MHFD offspring mice at different days of age before and after birth were significantly up-regulated,the expression level before birth was higher than that after birth,and expression level gradually decreased with the increase of day age.5.Both NRXN1 and NR2 A are candidate target genes of miR-125b-5p.NRXN1 and NR2 A protein levels in N2 A cells overexpressing miR-125b-5p were down-regulated.NRXN1 protein levels in the PFC of MHFD offspring mice was down-regulated,while NR2 A protein levels in the PFC of MHFD offspring mice was not significantly changed.Conclusion:1.Maternal high fat diet can induce autism-related behaviors in offspring mice and upregulate the expression level of miR-125b-5p in the PFC of offspring mice,and the expression level before birth was higher than that after birth;2.As the candidate target gene of miR-125b-5p,the expression of NRXN1 in the PFC of MHFD offspring mice was down-regulated by miR-125b-5p.3.High fat diet can up-regulate the expression level of miR-125b-5p in the adipose tissue of female mice;... |
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