Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia.
BACKGROUND
Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia.


METHODS
To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phosphate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly I:C-mice) were examined.


RESULTS
In juveniles, no difference was found between the poly I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). Increased dopamine (DA) turnover and decreased receptor binding of D2-like receptors, but not D1-like receptors, in the striatum were found in adult poly I:C-mice.


CONCLUSIONS
Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.
Ozawa
Kimiyoshi
K
Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. kimiyosi@faculty.chiba-u.jp
Hashimoto
Kenji
K
Kishimoto
Takashi
T
Shimizu
Eiji
E
Ishikura
Hiroshi
H
Iyo
Masaomi
M
D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D000914:Antibodies, Viral / Q000097:blood; D001921:Brain / Q000503:physiopathology; D003024:Clozapine / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D005556:Form Perception / Q000187:drug effects / Q000502:physiology; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology; D008694:Methamphetamine; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D015213:Neuroimmunomodulation / Q000502:physiology*; D009949:Orientation / Q000187:drug effects / Q000502:physiology; D011070:Poly I-C / Q000276:immunology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology*; D011270:Pregnancy, Animal / Q000276:immunology*; D011297:Prenatal Exposure Delayed Effects; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000503:physiopathology*; D014777:Virus Diseases / Q000276:immunology*
D000914:Antibodies, Viral; D016207:Cytokines; D008694:Methamphetamine; D003024:Clozapine; D011070:Poly I-C