The role of maternal microchimerism and prenatal stress for perinatal brain development and cognition

Epidemiological studies show that early childhood pre- and postnatal life events are predictive of certain disorders. Maternal vertically transferred markers, such as stress hormones and cytokines, play a fundamental role in affecting the development of the immune and nervous system. Those changes then increase the likelihood of emotional and cognitive impairments. Until know, maternal microchimeric cells (MMc) are a potential mechanism in the development of psychiatric and neurological diseases. Hereby, maternal microchimerism describes the presence of a small number of maternal cells in the fetal tissue, a phenomenon that takes place during pregnancy and persists into human and murine adulthood. The present thesis examines the link between MMc and fetal brain development as well as related ontogeny of neuronal networks and cognitive-behavioral changes in later life. The aim was to identify cellular and molecular mediators between a transfer of MMc to the fetal brain and postnatal cognitive changes as well as a possible influence of maternal stress.
With this aim, an existing mouse model for the identification of pregnancy-induced MMc was enhanced, so that the number of cells to be transferred can be modulated. Rag2-/-gc-/- C57BL/6 (CD45.2, H-2b/b) female mice were mated with Balb/c (CD45.1, H-2d/d) males. The offspring’s cells can then be quantified by flow cytometry through their heterozygous expression of parental markers (CD45.2.1, H-2b/d). Accordingly, maternal cells can be identified by CD45.2/CD45.1neg and H-2b/b/H-2d/dneg. In order to generate genetically identical offspring as control animals, the vice versa mating was used. The lack of T-, B-, and NK-cells in Rag2-/-gc-/- C57BL/6 dams prevents the transmission of the missing immune cells. In a second mouse model, regular C57BL/6 females were mated to Balb/c males, and the pregnant mouse was exposed to auditory stress on pregnancy days 10.5, 12.5 and 14.5. The first mating combination generates MMclow offspring, which have significantly less MMc in the brain at E18.5 and at P8 than the control animals MMcpos. The majority of the MMc in the brain acquire a distinct microglia phenotype in the course of the first postnatal week, with T and B cells also being present. At the same time, however, the MMclow animals show a significantly higher number of microglial cells in the E18.5 brain. Immunohistological studies on P8 show that the functional activity of the microglial cells is higher because they increasingly engulf synaptic vesicles in MMclow HP and PFC compared to MMcpos. These changes in synaptic connections led to a deterioration in oscillatory activity (4-100 Hz) in two brain areas (PFC and HP), which are associated with cognitive processes. MMclow offspring also showed poorer performance in ultrasonic vocalization. Restoring the immunocompetence of immunocompromised mothers during pregnancy largely restored the deterioration in the so-called MMclow+AT offspring. Furthermore, the prenatal stress exposure of the mice increases the transfer of MMc to the fetal brain, since significantly more MMc was shown at P8 compared to undisturbed control animals. This increase is due to more cells in female and non-male offspring and shows an increase in the microglia phenotype. Furthermore, the microglia cells of the offspring are increased in both males and females. This work shows that the transfer of the MMc into the fetal brain takes place during pregnancy. After birth, these cells differentiate into mainly macrophages of the central nervous system and play a central role in the design of the neuronal connection. Adverse influences during pregnancy, e.g. stress has the potential to change the phenotypes of these cells and, at the same time, the vulnerability to diseases.