Inter-breeder differences in prepulse inhibition deficits of C57BL/6J mice in a maternal immune activation model

Abstract

Genetic and environmental factors interact with each other to influence the risk of various psychiatric diseases; however, the intensity and nature of their interactions remain to be elucidated. We established a maternal infection model using polyinosinic-polycytidylic acid (Poly(I:C)) to determine the relationship between the maternal breeding environment and behavioral changes in the offspring. We purchased pregnant C57BL/6J mice from three breeders and administered Poly(I:C) (2 mg/kg) intravenously in their tail vein on gestation day 15. The offspring were raised to 8-12 weeks old and subjected to the acoustic startle tests to compare their startle response intensity, prepulse inhibition levels, and degree of the adaptation of the startle response. No statistical interaction between Poly(I:C) administration and sex was observed for prepulse inhibition; thus, male and female mice were analyzed together. There was a statistical interaction between the breeder origin of offspring and prepulse inhibition; the Poly(I:C) challenge significantly decreased prepulse inhibition levels of the offspring born to the pregnant dams from Breeder A but not those from the other breeders. However, we failed to detect significant inter-breeder differences in Poly(I:C) effects on startle response and on startle adaptation with the given number of mice examined. The rearing environment of mouse dams has a prominent effect on the Poly(I:C)-induced prepulse inhibition deficits in this maternal immune activation model.

Keywords: gene-environment; polyinosinic-polycytidylic acid; prepulse inhibition; schizophrenia; startle response.

FIGURE 1

The effect of dams' breeders on prepulse inhibition after administering Poly(I:C) to their dams. The inhibitory effects of prepulse sounds at 73, 76, 79, and 82 dB were assessed as PPI levels in pups born to pregnant C57BL/6J mice after raising them for 2‐3 months. On gestation day 15, pregnant mice from CLEA Japan (A; n = 17 for saline and n = 39 for Poly(I:C) from 3 and 6 dams, respectively), Charles River Japan (B; n = 21 for saline and n = 14 for Poly(I:C) both from 3 dams), and SLC Japan (C; n = 27 for saline and n = 24 for Poly(I:C) both from 5 dams) were challenged with Poly(I:C) or saline. Data are presented as mean ± SEM. PPI was observed in the inhibitory % of the main pulse‐triggered startle. *P < .05, planned multiple comparison was performed between saline and Poly(I:C) groups at each prepulse levels using Welch t test with the Holm's compensation

FIGURE 2

Inter‐breeder differences in sound startle response and adaptation. Employing the same sets of mice in Figure 1, we determined the intensity of their startle response (mV) to 120‐dB white noises (A‐C) and adaptation rates of the startle responses (%) to the 120‐dB noises (D‐F). The pregnant mice (C57BL/6J) were purchased from CLEA Japan (A, D), Charles River Japan (B, E), and SLC Japan (C, F). Data are presented as mean ± SEM. See statistical details in Table S1. In the startle intensity, there were an inter‐breeder difference between CLEA Japan and SLC Japan (⁺⁺ P < .01, Tukey HSD) and a sex difference in all breeders (^# P < .05, Welch t test with the Holm's compensation), which was irrespective of the Poly(I:C) effects