Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology.
BACKGROUND
Gene-environment interactions (GEI) are involved in the pathogenesis of mental diseases. We evaluated interaction between mutant human disrupted-in-schizophrenia 1 (mhDISC1) and maternal immune activation implicated in schizophrenia and mood disorders.


METHODS
Pregnant mice were treated with saline or polyinosinic:polycytidylic acid at gestation day 9. Levels of inflammatory cytokines were measured in fetal and adult brains; expression of mhDISC1, endogenous DISC1, lissencephaly type 1, nuclear distribution protein nudE-like 1, glycoprotein 130, growth factor receptor-bound protein 2, and glycogen synthase kinase-3beta were assessed in cortical samples of newborn mice. Tissue content of monoamines, volumetric brain abnormalities, dendritic spine density in the hippocampus, and various domains of the mouse behavior repertoire were evaluated in adult male mice.


RESULTS
Prenatal interaction produced anxiety, depression-like responses, and altered social behavior that were accompanied by decreased reactivity of the hypothalamic-pituitary-adrenal axis, attenuated serotonin neurotransmission in the hippocampus, reduced enlargement of lateral ventricles, decreased volumes of amygdala and periaqueductal gray matter and density of spines on dendrites of granule cells of the hippocampus. Prenatal interaction modulated secretion of inflammatory cytokines in fetal brains, levels of mhDISC1, endogenous mouse DISC1, and glycogen synthase kinase-3beta. The behavioral effects of GEI were observed only if mhDISC1 was expressed throughout the life span.


CONCLUSIONS
Prenatal immune activation interacted with mhDISC1 to produce the neurobehavioral phenotypes that were not seen in untreated mhDISC1 mice and that resemble aspects of major mental illnesses. Our DISC1 mouse model is a valuable system to study GEI relevant to mental illnesses.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA.
Bagrat
B
Abazyan
Jun
J
Nomura
Geetha
G
Kannan
Koko
K
Ishizuka
Kellie L
KL
Tamashiro
Frederick
F
Nucifora
Vladimir
V
Pogorelov
Bruce
B
Ladenheim
Chunxia
C
Yang
Irina N
IN
Krasnova
Jean Lud
JL
Cadet
Carlos
C
Pardo
Susumu
S
Mori
Atsushi
A
Kamiya
Michael W
MW
Vogel
Akira
A
Sawa
Christopher A
CA
Ross
Mikhail V
MV
Pletnikov
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D049229:Dendritic Spines / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019964:Mood Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011070:Poly I-C / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000523:psychology*; D013315:Stress, Psychological / Q000378:metabolism
D015306:Biogenic Monoamines; D002352:Carrier Proteins; D016207:Cytokines; C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D008869:Microtubule-Associated Proteins; C486015:Ndel1 protein, mouse; D009419:Nerve Tissue Proteins; D050822:Cytokine Receptor gp130; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D011070:Poly I-C; D003345:Corticosterone