Maternal immune activation in the early or late pregnancy leads to the different behavioral abnormalities of the adult offspring relevant to the schizophrenia

Abstract

BACKGROUND: Maternal infection increases the risk for schizophrenia in the offspring suggests that the maternal immune system plays a key role in the psychopathology of schizophrenia. In a mouse model, maternal immune activation (MIA) by injection of polyriboinosinic-polyribocytidilic acid (polyI:C) is known to precipitate a wide spectrum of behavioral, cognitive, and pharmacological abnormalities in adult offspring. PolyI:C leads to the pronounced production of pro-inflammatory cytokines. Specifically, the relative expression of cytokines in the fetal brains in response to maternal immune challenge may be an indirect mechanism by which MIA can alter fetal development. Our previous findings suggested that PolyI:C exposed earliest in gestation caused extensive deficit of integrity of fronto-striatallimbic circuits. Also, the early but not late prenatal immune challenge disrupts sensorimotor gating in adulthood in our study. In the present study, PolyI:C challenge on the early and late gestation was used as animal model of schizophrenia and immune responses in pregnant mice were assessed. In addition, locomotor activity, fear conditioning and pharmacological responses were evaluated in their adult offspring which relate with the different phenotypes in schizophrenia. METHODS: Pregnant mice were treated with saline or PolyI:C (5mg/kg, vol. of injection 5ml/kg) at gestation day 9 and day 17. Levels of inflammatory cytokines (interleukin 6: IL 6, IL 10, and tumor necrosis factor α: TNFα) were measured in serum of pregnant mice after 1hr PolyI:C challenge. The mice of adult offspring (CON=10, GD9 PolyIC=4, GD17 PolyIC=6) were injected with saline and returned to the open field for 30 min. Then, they were injected with D-amphetamine before being returned back to the open field for 90 min. Fear conditioning protocol: On the training day, mice (GD9 SAL=7, GD9 PolyIC=10; GD17 SAL+GD9 SAL=8, GD17 PolyIC=6) were placed into conditioning chamber for 6 min habituation, followed by 3 paired clicker (CS, 30 sec, 4Hz, 80 dB) and footshock (US, 2 sec, 0.5mA). After the final clicker/shock pairing in the chamber, mice continually stayed in the chamber for the extra 2 mins. Then context and cued test were measured after training for 24 hr and 48 hr. RESULTS: After 1hr exposure to PolyI:C markedly increased the serum protein levels of IL-6, IL-10 and TNF α in both gestation day condition compared to saline injection. One-way ANOVA showed a significant group difference in cytokine protein levels: IL 6: F(2,9)=6.254, p<0.05; IL 10: F(2,9)=51.430, p<0.0001; TNFα: F(2,9)=5.107, p<0.05. Post hoc comparisons were conducted showed that IL6 level in GD9 showed significant difference compared to control, TNFα level in GD17 showed significant higher compared to control, IL10 level showed significant increased in both GD9 and GD17 compared to control. The offspring of GD9 showed significant hyperactivity compared to control after saline injection, p<0.0001. Both GD9 and GD17 expressed the hypersensitive to amphetamine challenge compared to control: GD9, p<0.0001; GD17, p<0.05. Interestingly, GD9 MIA mice showed normal fear learning and memory. However, GD17 showed deficit of context test which is sensitive to hippocampal function. DISCUSSION: Present studies show that the time of MIA critically determines the pattern of behavioral abnormalities which may be indirectly caused by cytokine responses. PolyIC injection on GD9 increased locomotor activities and induced more sensitivity to amphetamine challenge which may relate with prenatal IL 6 immune response. GD17 but not GD9 showed deficit of context dependent fear memory.