Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron-microglia crosstalk, particularly CX3CL1-CX3CR1 and CD200-CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the "two-hit" hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1-CX3CR1 and CD200-CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the "second hit" wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200-CD200R system, while the changes of the CX3CL1-CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200-CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the "second hit" generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and "priming" microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200-CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.
Keywords: CD200–CD200R; CX3CL1–CX3CR1; lipopolysaccharide; microglia; prenatal immune challenge; schizophrenia; two-hit.