Changes in Dpysl2 expression are associated with prenatally stressed rat offspring and susceptibility to schizophrenia in humans

Lee,Hwayoung; Joo,Jaesoon; Nah,Seong-Su; Kim,Jong  Woo; Kim,Hyung-Ki; Kwon,Jun-Tack; Lee,Hwa-Young; Kim,Young  Ock; Kim,Hak-Jae

doi:10.3892/ijmm.2015.2161

Changes in Dpysl2 expression are associated with prenatally stressed rat offspring and susceptibility to schizophrenia in humans

Authors:
- Hwayoung Lee
- Jaesoon Joo
- Seong-Su Nah
- Jong Woo Kim
- Hyung-Ki Kim
- Jun-Tack Kwon
- Hwa-Young Lee
- Young Ock Kim
- Hak-Jae Kim
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Affiliations: Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea, Division of Rheumatology, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea, Department of Neuropsychiatry, School of Medicine, Kyunghee University, Seoul, Republic of Korea, Department of Psychiatry, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea, Development of Ginseng and Medical Plants Research Institute, Rural Administration, Eumseong, Republic of Korea
Published online on: April 1, 2015 https://doi.org/10.3892/ijmm.2015.2161
Pages: 1574-1586
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.

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