Background The bidirectional communication between neurons and microglia is fundamental for the homeostasis and biological function of the central nervous system. Maternal immune activation (MIA) is considered to be one of the factors affecting these interactions. Accordingly, MIA has been suggested to be involved in several neuropsychiatric diseases, including schizophrenia. The crucial regulatory systems for neuron-microglia crosstalk are the CX3CL1-CX3CR1 and CD200-CD200R axes. Methods We aimed to clarify the impact of MIA on CX3CL1-CX3CR1 and CD200-CD200R signalling pathways in the brains of male Wistar rats in early and adult life by employing two neurodevelopmental models of schizophrenia based on the prenatal challenge with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C). We also examined the effect of MIA on the expression of microglial markers and the profile of cytokines released in the brains of young offspring, as well as the behaviour of adult animals. Moreover, we visualized the localization of ligand-receptor systems in the hippocampal regions (CA1, CA3 and DG) and the frontal cortex of young rats exposed to MIA. The differences between groups were analysed using Student’s t test. Results We observed that MIA altered developmental trajectories in neuron-microglia communication in the brains of young offspring, as evidenced by the disruption of CX3CL1-CX3CR1 and/or CD200-CD200R axes. Our data demonstrated the presence of abnormalities after LPS-induced MIA in levels of Cd40 , Il-1β , Tnf-α , Arg1 , Tgf-β and Il-10 , as well as IBA1, IL-1β and IL-4, while after Poly I:C-generated MIA in levels of Cd40 , iNos , Il-6 , Tgf-β , Il-10 , and IBA1, IL-1β, TNF-α, IL-6, TGF-β and IL-4 early in the life of male animals. In adult male rats that experienced prenatal exposure to MIA, we observed behavioural changes resembling a schizophrenia-like phenotype. Conclusions Our study provides evidence that altered CX3CL1-CX3CR1 and/or CD200-CD200R pathways, emerging after prenatal immune challenge with LPS and Poly I:C, might be involved in the aetiology of schizophrenia.

: The bidirectional communication between neurons and microglia is fundamental for the proper functioning of the central nervous system (CNS). Chemokines and clusters of differentiation (CD) along with their receptors represent ligand-receptor signalling that is uniquely important for neuron – microglia communication. Among these molecules, CX3CL1 (fractalkine) and CD200 (OX-2 membrane glycoprotein) come to the fore because of their cell-type-specific localization. They are principally expressed by neurons when their receptors, CX3CR1 and CD200R, respectively, are predominantly present on the microglia, resulting in the specific axis which maintains the CNS homeostasis. Disruptions to this balance are suggested as contributors or even the basis for many neurological diseases. : In this review, we discuss the roles of CX3CL1, CD200 and their receptors in both physiological and pathological processes within the CNS. We want to underline the critical involvement of these molecules in controlling neuron – microglia communication, noting that dysfunctions in their interactions constitute a key factor in severe neurological diseases, such as schizophrenia, depression and neurodegeneration-based conditions.

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.