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

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.

Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia

“…Simultaneously, the protein levels of the CX3CL1-CX3CR1 pair were upregulated in the frontal cortex of these animals. The additional injection of Poly I:C in adulthood decreased cortical Cx3cr1 expression and increased hippocampal CX3CL1 level in offspring without impairment in PPI [174].…”

“…The additional acute challenge with LPS later in life, according to the “two-hit” hypothesis of schizophrenia, decreased levels of hippocampal CX3CL1 in rats with altered PPI and cortical CX3CR1 in animals without such behavioral deficiency [ 173 ]. In similar experimental conditions, yet applying MIA with Poly I:C, the mRNA expression of both Cx3cl1 and Cx3cr1 was reduced in the hippocampus of adult descendants without PPI deficit [ 174 ]. Simultaneously, the protein levels of the CX3CL1–CX3CR1 pair were upregulated in the frontal cortex of these animals.…”

“…Simultaneously, the protein levels of the CX3CL1–CX3CR1 pair were upregulated in the frontal cortex of these animals. The additional injection of Poly I:C in adulthood decreased cortical Cx3cr1 expression and increased hippocampal CX3CL1 level in offspring without impairment in PPI [ 174 ]. The results came from the experiments on Sprague-Dawley rats, which suggests that the different strains exert notable effects on the outcome of examinations in MIA models.…”

The emerging role of mechanical and topographical factors in the development and treatment of nervous system disorders: dark and light sides of the force

“…com) based on reference nos. [43,66,86,87,92] study differences in growth cone behaviour between central nervous system neurons (hippocampal) and the peripheral nervous system (dorsal root ganglion-DRG). DRG neurons are characterized by stiffness-dependent neurite outgrowth and generate higher forces than hippocampal neurons, and neurite outgrowth is independent of substrate stiffness [58].…”

“…A potential strategy for treating the effects of ischaemic stroke is the modulation of receptors of selected chemokines present on microglia [82]. These include CCL2, CXCL12 receptors, and ultimately fractalkine receptor (CX3CR1), expressed only on microglia but not neurons and astrocytes and thus a frequent subject of interest in such investigations [83][84][85][86]. Thanks to a specific location, the CX3CL1-CX3CR1 system plays an important role in the interaction between neurons and microglia, thus constituting a system of communication between these cells [87][88][89].…”