Abstract
Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the “second hit” in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.
Highlights
Multiple lines of evidence suggest that the aetiology of schizophrenia involves aberrant neurodevelopmental processes [1,2,3]
Considering the alterations in the pro- and anti-inflammatory factors, we examined the effect of maternal immune activation (MIA) and the acute systemic injection of polycytidylic acid (Poly I):C in adulthood on the mRNA levels of neuronal ligands (Cx3cl1, Cd200) and their corresponding microglial receptors (Cx3cr1, Cd200r) in the frontal cortices and hippocampi of male offspring (Table 3)
Amplification was performed in a 20-μL mixture consisting of complementary DNA (cDNA), which was used as the polymerase chain reaction (PCR) template (1 μL), 1× FastStart Universal Probe Master (Rox) mix containing 250 nM hydrolysis probe labelled with the fluorescent reporter dye [fluorescein (FAM)] at the 5 -end and a quenching dye at the 3 -end (10 μL), and, the remainder of PCR-grade distilled water (8 μL)
Summary
Multiple lines of evidence suggest that the aetiology of schizophrenia involves aberrant neurodevelopmental processes [1,2,3]. One of the crucial mechanisms involved in the regulation of microglial reactivity is based on proper communication between neurons and microglia This interaction is executed mainly via the specialized, endogenous protein systems CX3CL1-CX3CR1 and CD200-CD200R, which represent unique ligand-receptor axes [35,36,37]. The CD200-CD200R system plays a regul3atoof r2y6 role in the brain by affecting the proliferation and apoptosis of microglial cells [52] In this proof-of-concept study, we explored the hypothesis that acute treatment with. We showed that MIA did not induce alterations either in the time or the number of non-aggressive behaviours; it decreased the time and the number of aggressive activities of the male offspring at PND90, thereby limiting this type of interaction (Table 1). MIA control 0.50 ± 0.384.*50 ± 1.00 2.00 ± 1.3196.0*0 ± 5.01 18.75 ±181.8.884± 2.63 70.1653.6±3 1±01.72.864
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