Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Abstract

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.

Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia

“…Thus, the negative correlation between novelty-related behaviour, immobility, and climbing time in the FST, which has been postulated by some authors [ 83 , 84 ], has been confirmed. Our present results are consistent with previously published data from the MIA model induced by the administration of the bacterial endotoxin lipopolysaccharide (LPS) [ 85 ] as well as with the results of other authors obtained in neurodevelopmental models of schizophrenia [ 86 ]. These observations positively validate the Poly I:C MIA model in the context of the presence of positive symptoms in animals, which can be compared with the psychomotor agitation present in some schizophrenic patients [ 87 ].…”

“…In our previous study, we demonstrated that elevated IL-6 levels preceded the manifestation of schizophrenia-like disturbances [ 130 ]. Additionally, acute IL-6 treatment was shown to trigger a deficit in sensorimotor gating in mice [ 19 ], while in Sprague-Dawley rats in the LPS-induced MIA model, elevated Il-6 expression participated in the manifestation of the PPI deficit, negative regulation of the CD200-CD200R axis, and microglia priming [ 85 ]. Based on the mentioned data, the time of the tests performed after applying the “second hit” could have influenced the rate of transcription and translation processes as well as the insufficient increase in the level of Il-6 and the lack of expected behavioural effects in offspring with “primed microglia”.…”

The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Exhibits Anti-Inflammatory Activity in LPS-Stimulated Organotypic Hippocampal Cultures

“…Thus, the equipoise between IL-10 induction and the amount of pro-IL1β potentially determines the final level of IL-1β [ 45 ]. IL-10 may also exert an anti-inflammatory effect through the fractalkine receptor (CX3CR1), which is mainly expressed in microglial cells [ 46 , 47 ]. Consistent with the results reported by Cunha et al [ 48 ], in the present study, we observed that LPS diminishes Cx3cr1 expression, but only in WT cultures.…”

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

“…Some chemokines (underlined here) that are altered in schizophrenia can bind to multiple receptors and they all act through increasing calcium transients. Based on [ 10 , 11 , 261 , 264 , 267 , 268 , 269 , 275 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 ].…”