Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood.
Gene-environment interaction may play a role in the etiology of schizophrenia. Transgenic mice expressing dominant-negative DISC1 (DN-DISC1 mice) show some histological and behavioral endophenotypes relevant to schizophrenia. Viral infection during neurodevelopment provides a major environmental risk for schizophrenia. Neonatal injection of polyriboinosinic-polyribocytidylic acid (polyI:C), which mimics innate immune responses elicited by viral infection, leads to schizophrenia-like behavioral alteration in mice after puberty. To study how gene-environmental interaction during neurodevelopment results in phenotypic changes in adulthood, we treated DN-DISC1 mice or wild-type littermates with injection of polyI:C during the neonatal stage, according to the published method, respectively, and the behavioral and histological phenotypes were examined in adulthood. We demonstrated that neonatal polyI:C treatment in DN-DISC1 mice resulted in the deficits of short-term, object recognition, and hippocampus-dependent fear memories after puberty, although polyI:C treatment by itself had smaller influences on wild-type mice. Furthermore, polyI:C-treated DN-DISC1 mice exhibited signs of impairment of social recognition and interaction, and augmented susceptibility to MK-801-induced hyperactivity as compared with vehicle-treated wild-type mice. Of most importance, additive effects of polyI:C and DN-DISC1 were observed by a marked decrease in parvalbumin-positive interneurons in the medial prefrontal cortex. These results suggest that combined effect of neonatal polyI:C treatment and DN-DISC1 affects some behavioral and histological phenotypes in adulthood.
Ibi
Daisuke
D
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Nagai
Taku
T
Koike
Hiroyuki
H
Kitahara
Yuko
Y
Mizoguchi
Hiroyuki
H
Niwa
Minae
M
Jaaro-Peled
Hanna
H
Nitta
Atsumi
A
Yoneda
Yukio
Y
Nabeshima
Toshitaka
T
Sawa
Akira
A
Yamada
Kiyofumi
K
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology*; D049109:Cell Proliferation; D003214:Conditioning, Classical / Q000502:physiology; D016291:Dizocilpine Maleate / Q000633:toxicity; D005239:Fear / Q000502:physiology; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D006624:Hippocampus / Q000276:immunology* / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D007369:Interferon Inducers / Q000008:administration & dosage; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D011070:Poly I-C / Q000008:administration & dosage; D021641:Recognition, Psychology / Q000502:physiology; D013216:Reflex, Startle / Q000235:genetics / Q000276:immunology; D055139:Sensory Gating / Q000235:genetics / Q000276:immunology; D012919:Social Behavior; D013194:Staining and Labeling
C498794:Disc1 protein, mouse; D007369:Interferon Inducers; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D016291:Dizocilpine Maleate; D011070:Poly I-C