title: A heterozygous deletion in the glutamate decarboxylase 67 gene enhances maternal and fetal stress vulnerability.
abstract: Both down-regulation of glutamate decarboxylase 67 (GAD67) and maternal exposure to severe stress during pregnancy can increase the risk of schizophrenia and related psychotic disorders in the offspring. To investigate a gene-environment interaction, we performed the restraint-and-light stress to pregnant GAD67-GFP knock-in (GAD67(+/GFP)) and wild-type (GAD67(+/+)) mice three times a day for 45 min per session during gestational day (G) 15.0-17.5. The stress hormone (corticosterone) level of pregnant GAD67(+/GFP) mice (the overall GABA content is reduced because of the destruction of one allele of the endogenous GAD67 gene) was higher than that of GAD67(+/+), even without stress. The fetal body weights (GAD67(+/+)) in the GAD67(+/GFP) mothers were lower than those in the GAD67(+/+) mothers. GAD67(+/GFP) fetuses exhibited higher corticosterone (CORT) levels than GAD67(+/+) fetuses, even in non-stressed GAD67(+/+) mothers. Fetal body weight-decreases and CORT-increases by maternal stress (GAD67(+/+) mother) were significantly more in the GAD67(+/GFP) fetuses than the GAD67(+/+) fetuses. These results indicate that a GAD67 heterozygous deletion itself enhances vulnerability by many aspects, e.g., maternal stress, maternity, and being in utero. Thus, an abnormality in GAD67 could interact with environmental risk factors of psychiatric disorders, including schizophrenia.
authors.affiliation: Department of Physiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Uchida
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oki
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000097:blood; D005260:Female; D005333:Fetus; D055879:Gene Knock-In Techniques; D005968:Glutamate Decarboxylase / Q000172:deficiency / Q000235:genetics*; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology*; D013315:Stress, Psychological / Q000150:complications* / Q000503:physiopathology
chemical_list: D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D003345:Corticosterone