long-term effects of prenatal immune activation on depression-like behavior in the mouse

Mood disorders are among the most prevalent and debilitating forms of mental illnesses in Austria and world-wide. These disorders are not only burdensome and even life-threatening for the affected individuals, but are also of significant socio-economic impact. Early life events may have a profound effect on the physiological and psychological development of an organism. Evidence in literature suggests that traumatic events during early stages of life, including the pre- and perinatal period are associated with psychiatric morbidity later in life. Among the multiple potential early life adversities, several lines of evidences suggest infections during pregnancy as powerful factor contributing to the development of mental illnesses later in life, most prominently related to the pathophysiology of schizophrenia and autism. However, the role of infection-related maternal immune activation (MIA) in the etiology of depression and its neurobiological basis are insufficiently investigated. The long term objective of this study is therefore to investigate whether the effects of intrauterine immune activation on the development of depression-like behavior later in life and to identify its morphological, cellular and molecular correlates. To this end, we will therefore test the following three basic hypotheses in the mouse model: First, that the depression-like behavior in adulthood, associated cognitive deficits and alterations in adult hippocampal neurogenesis resulting from MIA are due to alterations in neurotrophic signaling cascade of Vascular Endothelial Growth Factor A (VEGFA). Second, that MIA induces long-lasting anatomical structural changes in the offspring brain. Third, that MIA influences stress sensitivity and response to antidepressant treatment later in life in interaction with the specific genetic background. The proposed project provides the first comprehensive characterization of the effects of maternal immune activation on depression at the behavioral, cellular and molecular level in the mouse model system. Results from this study may have implications for several branches of basic (neuro) sciences and moreover could have considerable translational value. Data obtained may form the basis for respective research studies in the human population in the fields of immunology, psychology and psychiatry.

Depression is one of the most common and severe mental illnesses whose neurobiological underpinnings remain incompletely understood. The fundamental influences of early life experiences, including the pre-, peri- and early postnatal periods on the neuronal development of the offspring with relevance for emotional functions and associated pathologies are well described. In this project we generated important insights into the impact of gestational infections on the development of depression in the offspring. Using a mouse model for maternal immune activation (MIA) we demonstrated augmented depression-like behavior in the adult offspring which was accompanied by an alteration in adult hippocampal neurogenesis together with reduced support by the growth factor VEGF (Khan et al. 2014). Using the same preclinical paradigm we also provided evidence for a disruption of maternal care behavior in MIA dams after birth (Ronovsky et al. 2016). In light of the known relevance of maternal care for offspring neuronal development with impact on emotional behaviors later in life and the possibility for transgenerational transmission we further examined maternal care behavior in the adult MIA female of the first (F1) and depression-like behavior of the second (F2) generation offspring. An impact of MIA on maternal care in the F1 generation with possible impact on depression-like behavior in the F2 generation was observed in two distinct inbred mouse strains (Ronovsky et al. 2016; Berger et al. 2018). These long-lasting, generation- spanning consequences of MIA suggest an involvement of epigenetic mechanisms. This possibility was tested with regards to the relevance of selected miRNAs as well as concerning changes in histone acetylation. An analysis of expressional levels of specific miRNA species in the brain of F1 and F2 offspring did not provide evidence for relevant changes in the MIA group as compared to controls (Berger et al. 2018). Interestingly, modulations of the global histone acetylation profile in MIA offspring brain together with specific changes at the promoter and in the expression of the serotonin transporter (SERT) gene were detected (Reisinger et al. 2016). A follow-up project has been designed in order to further examine histone modifications in the brain of MIA offspring of the first, second and third generation in greater detail.