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Clinical Trial
, 35 (6), 1574-86

Changes in Dpysl2 Expression Are Associated With Prenatally Stressed Rat Offspring and Susceptibility to Schizophrenia in Humans

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Clinical Trial

Changes in Dpysl2 Expression Are Associated With Prenatally Stressed Rat Offspring and Susceptibility to Schizophrenia in Humans

Hwayoung Lee et al. Int J Mol Med.

Abstract

Exposure to stress during critical periods of fetal brain development is an environmental risk factor for the development of schizophrenia in adult offspring. In the present study, a repeated-variable stress paradigm was applied to pregnant rats during the last week of gestation, which is analogous to the second trimester of brain development in humans. Behavioral and proteomic analyses were conducted in prenatally-stressed (PNS) adult offspring and non-stressed (NS) adult controls. In the behavioral tests, grooming behavior in the social interaction test, line-crossing behavior in the open field test, and swimming behavior in the forced swimming test were decreased in the PNS group. Western blot analysis and immunohistochemical analysis revealed that the expression of dihydropyrimidinase-like 2 (Dpysl2) or collapsin response mediator protein 2 (Crmp2) was downregulated in the prefrontal cortex and hippocampus of rats in the PNS group. Subsequently, single-nucleotide polymorphisms (SNPs) of the human dihydropyrimidinase-like 2 (DPYSL2) gene were analyzed in a population. Two functional SNPs (rs9886448 in the promoter region and rs2289593 in the exon region) were associated with susceptibility to schizophrenia. The present findings demonstrated that the downregulation of genes such as Dpysl2 and Dypsl3 in a rat model of prenatal stress may affect subsequent behavioral changes and that polymorphisms of the DPYSL2 gene in humans may be associated with the development of schizophrenia. Taken together with previous studies investigating the association between the DPYSL2 gene and schizophrenia, the present findings may contribute additional evidence regarding developmental theories of the pathophysiology of schizophrenia.

Figures

Figure 1
Figure 1
Behavioral response in the forced swim test. Comparison between NS and PNS offspring (n=10 in each group). Marks indicate a decrease in swimming. Data are presented as means ± SEM. *P<0.05. NS, non-prenatal stressed offspring; PNS, prenatal stressed offspring; SEM, standard error of the mean.
Figure 2
Figure 2
Protein profiles of two-dimensional gel electrophoresis. FC, prefrontal cortex; Hipp, hippocampus; NS, non-prenatal stressed offspring; PNS, prenatal stressed offspring.
Figure 3
Figure 3
Two-dimensional gel electrophoresis patterns of protein expression in rat brains for two selected proteins. FC, prefrontal cortex; Hipp, hippocampus; NS, non-prenatal stressed offspring; PNS, prenatal stressed offspring. Arrowheads are protein spots, showing different changes among the groups.
Figure 4
Figure 4
Western blot analysis of Dpysl2 expression in the brains of PNS-induced rats. (A) Dpysl2 expression was detected by western blotting with Actb used as an internal control. PNS rats exhibited decreased Dpysl2 expression in the prefrontal cortex and hippocampus. (B) Quantitative analysis of western blot data for Dpysl2 expression showing a significant difference in Dpysl2 levels in PNS vs. control rat brains (*P<0.05 compared with the NS group in the prefrontal cortex and hippocampus). Dpysl2, dihydropyrimidinase-like 2; FC, prefrontal cortex; Hipp, hippocampus; NS, non-prenatal stressed offspring; PNS, prenatal stressed offspring; SD, standard deviation.
Figure 5
Figure 5
Western blot analysis of Dpysl3 expression in the brains of PNS-induced rats. (A) Dpysl3 expression was detected by western blotting with Actb used as an internal control. PNS rats exhibited decreased Dpysl3 expression in the prefrontal cortex and hippocampus. (B) Quantitative analysis of western blot data for Dpysl3 expression showing a significant difference in Dpysl3 levels in PNS vs. control rat brains (*P<0.05 compared with the NS group in the prefrontal cortex and hippocampus). Dpysl3, dihydropyrimidinase-like 3; FC, prefrontal cortex; Hipp, hippocampus; NS, non-prenatal stressed offspring; PNS, prenatal stressed offspring; SD, standard deviation.
Figure 6
Figure 6
Immunohistochemical analysis of Dpysl2 expression in the brains of PNS-induced rats. (A) Confocal microscopic image showing immunofluorescent staining for Dpysl2 (anti-Dpysl2, red, Cy3) with DAPI in the prefrontal cortex and hippocampus. Fluorescent staining revealed decreased Dpysl2 in these regions. Scale bar, FC; 50 Hipp; 100 μm. (B) Optical densities of Dpysl2 signals in immunostained prefrontal cotex and hippocampus sections from (*P<0.05 compared with the NS group in the prefrontal cortex and hippocampus). Dpysl2, dihydropyrimidinase-like 2; FC, prefrontal cortex; Hipp, hippocampus; NS, non-prenatal stressed offspring; PNS, prenatal stressed offspring; SD, standard deviation.

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