Transgenerational Transmission and Modification of Behavioral Deficits Induced By Prenatal Immune Activation

Background:  It has been demonstrated that environmentally induced brain dysfunctions are not solely expressed by the individuals directly exposed, but can also be transmitted to the offspring, sometimes across multiple generations. 

Objectives:  Here we explored whether such transgenerational effects can be induced by prenatal infection, an environmental risk factor of autism and related neurodevelopmental disorders. 

Methods:  We used a well-established mouse model of prenatal immune activation, which has been shown to induce multiple behavioural deficits relevant to autism and related disorders. Pregnant mice (F0) were injected with the viral mimetic poly(I:C) (5 mg/kg) or control solution in early pregnancy (gestation day 9), and the behavioral effects were tested in the F1 generation. To examine whether such deficits can be transmitted to subsequent generations, we generated F2 and F3 offspring by inter-crossing F1 and F2 offspring, respectively. We performed behavioral testing in adult F1, F2 and F3 offspring and exploited transcriptional profiling to determine gene expression in the prefrontal cortex (PFC) and amygdala (AMY) of F1 and F2 mice using next generation sequencing.

Results:  Behavioral analyses in F1, F2 and F3 offspring revealed that deficits in social interaction and cued fear, which emerge in F1 offspring, are also present in the F2 and F3 generation. F1 offspring also showed increased sensitivity to the psychostimulant drug amphetamine. Interestingly, the F2 and F3 generation displayed the opposite pattern, namely reduced amphetamine sensitivity. Deficits in sensorimotor gating, which are typically observed in the F1 generation, were not present in F2 and F3 offspring. RNA-sequencing analysis revealed a total number of 227 genes that are differentially expressed in F1 PFC poly(I:C) versus controls, 359 in F2 PFC poly(I:C) versus controls and 1226 genes in F1 Amy as well as 1665 genes in F2 Amy poly(I:C) versus controls. Out of the differentially expressed genes in F1 and F2 PFC, a total number of 12 genes are affected in both F1 and F2 brains. In the Amy, 415 genes are overlapping between F1 and F2 brains.

Conclusions:  Our findings demonstrate that behavioral deficits induced by prenatal infection can be transmitted and modified across subsequent generations. Furthermore, analysis of the transcriptome in F1 and F2 Amy and PFC revealed differential gene expression in poly(I:C) versus control animals in F1 as well as F2 animals. Future experiments will examine the possibility that the behavioral abnormalities and the differences in gene expression following prenatal immune activation are transmitted to subsequent generations via modifications in the epigenetic machinery.