Susceptibility and Plasticity following Prenatal Infection

Lead: Several epidemiological studies confirm the connection between prenatal infection and heightened risk for the development of psychiatric disorders, such as schizophrenia, autism or depression later in life. However, it remains unclear, why prenatal infections lead to development of such illnesses in some cases, while other individuals do not display any negative alterations and appear to be resilient. The overall goal of this project is to examine the biological basis of this resilience and its generation-spanning plasticity. Aims of the research project: Our research in a well-established mouse model has shown that even in genetically homogenous mice, not every animal is affected equally by the consequences of prenatal infection and that resilient individuals exist. We know from our earlier work that the effects of prenatal infection not only impact on direct offspring but may also impinge on the progeny in subsequent generations . Building on this knowledge, the current project is designed to explore the molecular signature of resilience by concentrating on epigenetic changes and the relevance of chromatin structure in this context. Furthermore, we will address the plasticity of such alterations across generations and in reaction to additional environmental influences. Scientific and societal context of the research project: Options for the therapeutic management of psychiatric disorders such as schizophrenia, depression and autism remain unsatisfactory to date. Understanding the molecular changes resulting from prenatal infection, specifically in resilient versus susceptible individuals is therefore of great importance for the development of novel and alternative therapeutic strategies against some of the most prevalent and debilitating mental illnesses. Preventive approaches could reduce the development and transmission of these diseases over generations and are thus of high socioeconomic relevance.

This project explored how a purified version of a compound called Poly(I:C), commonly used to mimic viral infections during pregnancy in animal studies, affects the brain and behavior of offspring. The goal was to better understand how infections during pregnancy might lead to mental health conditions such as autism or schizophrenia later in life. The researchers used a specially refined form of Poly(I:C) with low molecular weight, which is thought to produce more consistent results and fewer negative effects during pregnancy. They tested this compound in pregnant mice at two separate, highly experienced laboratories - one in Vienna and the other in Zurich - to see how well the results matched. Interestingly, both labs observed similar physical responses in the pregnant mice, such as signs of sickness and elevated immune markers (cytokines), and even changes in the brains of unborn mice. However, only in Zurich did the offspring later show the expected changes in behavior, specifically reduced sociability - a trait often linked to disorders like autism. In Vienna, the same treatment had no impact on offspring behavior, even when the dosage was increased or tested across multiple generations. This surprising difference shows that environmental factors - such as lab equipment, light cycles, food, housing conditions, or even the microbiome - may subtly influence how a developing brain responds to an immune challenge. These "invisible" influences make it difficult to create a one-size-fits-all experimental model, even when every effort is made to standardize procedures. The study has important implications for science and medicine. It urges researchers to go beyond measuring just immune reactions in mothers and fetuses and to carefully monitor offspring behavior when developing or adjusting experimental models. This could lead to better, more reliable models for studying mental health conditions. It also highlights the need for more transparent and precise documentation in laboratory research to improve reproducibility and understanding. Potential Applications: Better experimental models for studying the roots of neurodevelopmental disorders. Improved reproducibility in behavioral neuroscience research. Insights into how prenatal health and the environment influence long-term mental health.