Epigenetic and transgenerational mechanisms in infection-mediated neurodevelopmental disorders

Abstract

Prenatal infection is an environmental risk factor for various brain disorders with neurodevelopmental components, including autism spectrum disorder and schizophrenia. Modeling this association in animals shows that maternal immune activation negatively affects fetal brain development and leads to the emergence of behavioral disturbances later in life. Recent discoveries in these preclinical models suggest that epigenetic modifications may be a critical molecular mechanism by which prenatal immune activation can mediate changes in brain development and functions, even across generations. This review discusses the potential epigenetic mechanisms underlying the effects of prenatal infections, thereby highlighting how infection-mediated epigenetic reprogramming may contribute to the transgenerational transmission of pathological traits. The identification of epigenetic and transgenerational mechanisms in infection-mediated neurodevelopmental disorders appears relevant to brain disorders independently of existing diagnostic classifications and may help identifying complex patterns of transgenerational disease transmission beyond genetic inheritance. The consideration of ancestral infectious histories may be of great clinical interest and may be pivotal for developing new preventive treatment strategies against infection-mediated neurodevelopmental disorders.

Figure 1

Post-acute pathophysiological effects of maternal infection during pregnancy. Some infectious pathogens (for example, rubella virus, cytomegalovirus, herpes simplex virus-2 and Toxoplasma gondii) can be vertically transmitted and lead to congenital infections, which in turn can result in severe developmental deficits. Maternal infection during pregnancy can further induce a number of pathophysiological responses, even if the pathogen is not vertically transmitted. These responses include the production of soluble immune factors such as cytokines and other mediators of inflammation, as well as reactive oxygen species. Some of these factors might cross the placental barrier and enter the fetal environment, thereby causing fetal inflammation and oxidative stress. Maternal infection during pregnancy can further induce inflammatory response in the placenta and cause placental insufficiency, which in turn can cause fetal hypoxemia. In addition, infection can cause (temporary) states of macronutrient and micronutrient deficiency, which limits the fetal availability of essential nutrients necessary for normal fetal development and growth. Finally, maternal infection during pregnancy can modify the microbial composition of the placenta, which might alter the development of the offspring’s microbiome (not shown).

Figure 2

Schematic representation of major epigenetic mechanisms. The DNA–protein complex is referred to as chromatin. The functional unit of the chromatin is the nucleosome, which is composed of DNA wrapped around a core octamer of histone proteins. The DNA–histone interaction occurs at the N-terminal tails of these histones, which face outward and are sites for epigenetic marking known as histone modifications. These modifications represent a first major epigenetic mechanism modulating gene expression and involve methylation, phosphorylation, acetylation, ubiquitylation and sumoylation. DNA methylations at cytosine rings, typically found at CpG dinucleotides, are another important epigenetic mark that can influence gene expression. Finally, micro-RNAs (miRNAs), a class of small, non-coding RNAs, can control target gene expression post-transcriptionally. CpG, cytosine–phosphodiester–guanine.

Figure 3

Summary of the transgenerational transmission and modification of behavioral deficits induced by prenatal immune activation. The use of a mouse model of viral-like immune activation, which was induced by maternal treatment with the viral mimetic poly(I:C), led to the recent discovery of transgenerational effects following prenatal immune activation (for details, see Weber-Stadlbauer et al.). In this model, reduced sociability and increased fear-related behavior were similarly present in first-generation (F1) and second-generation (F2) offspring of immune-challenged ancestors. Sensorimotor gating impairments were confined to the direct descendants of infected mothers, whereas increased behavioral despair emerged as a novel phenotype in the second generation. The transgenerational effects were transmitted via the paternal lineage (not shown) and were stable until the third generation (F3), demonstrating transgenerational non-genetic inheritance of pathological traits following prenatal immune activation.