| Objectives To analyze the changes in the expression levels of the entire cerebral cortex and hippocampus of BTBR-PAH enu2（PKU）mice,exploring the mechanism of PKU cognitive impairment,and looking for potential biological markers of brain injury related to PKU cognitive impairment,it provides theoretical basis for designing targeted drugs to improve cognitive function.Methods（1）Passage and genotype identification of BTBR-PAH enu2（PKU）mice.（2）Different diet programs intervene in wild type（WT）and PKU mice,the intervention time is 9 weeks.According to the intervention program,they are divided into WT,PKU and LPD PKU mice.（3）Using gene chip technology to detect the whole genome expression profile of the cerebral cortex and hippocampus of three groups of diet intervention mice.（4）Perform bioinformatics analysis on the expression profile results to screen for differential genes and signaling pathways related to cognitive function.Results（1）Through the passage of BTBR-PAH enu2 mice,the DNA sequencing of the PAH gene of the progeny mice was completed,and three types of wild-type,homozygous and heterozygous were screened.（2）Before the dietary intervention of PKU mice,their blood Phe（760.96±32.53μmol/L）was significantly higher than that of WT mice（41.92±3.95μmol/L）（P<0.01）;At the third week of intervention,the blood Phe（40.07±16.04μmol/L）in the LPD PKU group decreased to the same level as the WT mice（P>0.05）;There was no significant difference between the blood Phe（60.12±28.26μmol/L）of mice in LPD PKU group and WT mice at the 6th week of intervention（P>0.05）;There was no significant difference between the blood Phe（46.45±22.04μmol/L）of LPD PKU group and WT mice at the 9th week of intervention（P>0.05）.（3）After 9 weeks of dietary intervention,changes in the expression profiles of the whole cerebral cortex and hippocampus in each group:（1）In the cerebral cortex:there are 403 differential genes（up-regulated 226,down-regulated 177）between PKU and WT mice,730 differential genes（up-regulated 461,down-regulated 279）between LPD PKU and WT mice,1139differential genes（up-regulated 490,down-regulated 649）between LPD PKU and PKU mice;（2）In hippocampus:there are 23 differential genes（up-regulated 12,down-regulated11）between PKU and WT mice,24 differential genes（up-regulated 10,down-regulated14）between LPD PKU and WT mice,30 differential genes（up-regulated 14 and down-regulated 16）between LPD PKU and PKU mice.（4）Bioinformatic analysis of expression profile results:（1）MAPK signaling pathway and dopaminergic synaptic signaling pathway in the cerebral cortex are significantly enriched in the differentially expressed genes of the three groups of mice;（2）Fos in the MAPK signaling pathway and Drd4 and Drd5 in the dopaminergic synaptic pathway are the differentially expressed genes that coexist in the three groups of mice,among them,compared with WT mice,Fos was down-regulated in PKU and LPD PKU mice,and PKU was down-regulated more significantly;Drd4 was up-regulated in both PKU and LPD PKU mice,and PKU was more up-regulated;Drd5 was up-regulated in PKU,Lowered in LPD PKU.Conclusion（1）The gene expression profiles of PKU mice and LPD PKU mice cerebral cortex and hippocampus are significantly different from those of WT mice;（2）MAPK signaling pathway and dopaminergic synaptic signaling pathway in the cerebral cortex are significantly enriched in the differentially expressed genes of the three groups of mice,Fos in the MAPK signaling pathway and Drd4 and Drd5 in the dopaminergic synaptic pathway are the differentially expressed genes that coexist in the three groups of mice.Given that MAPK signaling pathways and dopaminergic synaptic pathways are associated with changes in synaptic plasticity of cognitive impairment,we speculate that abnormal expression of Fos in the MAPK signaling pathway and Drd4 and Drd5 in the dopaminergic synaptic pathway of the cerebral cortex may be involved in the development of PKU cognitive impairment. |
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