Prenatal Immune Challenge Differentiates the Effect of Aripiprazole and Risperidone on CD200–CD200R and CX3CL1–CX3CR1 Dyads and Microglial Polarization: A Study in Organotypic Cortical Cultures

Jun 27, 2024Life (Basel, Switzerland)

Prenatal Immune Stress Changes How Aripiprazole and Risperidone Affect Brain Immune Signals and Microglial Response in Cortical Tissue

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Abstract

Maternal immune activation (MIA) diminished the mRNA level of key regulatory components in organotypic cortical cultures.

MIA affects the response of organotypic cortical cultures (OCCs) to additional stimulation with lipopolysaccharide (LPS).
LPS downregulated the expression of specific genes and altered the mRNA levels of pro- and anti-inflammatory markers in both control and MIA OCCs.
Risperidone treatment increased the expression of certain regulatory components in MIA OCCs.
Aripiprazole elevated gene levels in control OCCs and showed a more pronounced effect on pro- and anti-inflammatory cytokines compared to risperidone in MIA OCCs.
Both antipsychotics limited the increase in pro-inflammatory factors generated by LPS and enhanced the levels of anti-inflammatory components under certain conditions.

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Microglia are the primary innate immune cells of the central nervous system and extensively contribute to brain homeostasis. Dysfunctional or excessive activity of microglia may be associated with several neuropsychiatric disorders, including schizophrenia. Therefore, we examined whether aripiprazole and risperidone could influence the expression of theandaxes, which are crucial for the regulation of microglial activity and interactions of these cells with neurons. Additionally, we evaluated the impact of these drugs on microglial pro- and anti-inflammatory markers (,,,,,,and) and cytokine release (IL-6, IL-10). The research was executed in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those exposed to maternal immune activation (MIA OCCs), which allows for the exploration of schizophrenia-like disturbances in animals. All experiments were performed under basal conditions and after additional stimulation with lipopolysaccharide (LPS), following the "two-hit" hypothesis of schizophrenia. We found that MIA diminished the mRNA level ofand affected the OCCs' response to additional LPS exposure in terms of this parameter. LPS downregulated theexpression and profoundly changed the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Risperidone increasedexpression in MIA OCCs, while aripiprazole treatment elevated the gene levels of thedyad in control OCCs. The antipsychotics limited the LPS-generated increase in the expression of proinflammatory factors (and) and enhanced the mRNA levels of anti-inflammatory components (and) of microglial polarization, mostly in the absence of the MIA procedure. Finally, we observed a more pronounced modulating impact of aripiprazole on the expression of pro- and anti-inflammatory cytokines when compared to risperidone in MIA OCCs. In conclusion, our data suggest that MIA might influence microglial activation and crosstalk of microglial cells with neurons, whereas aripiprazole and risperidone could beneficially affect these changes in OCCs. Cd200-Cd200r Cx3cl1-Cx3cr1Cd40Il-1β Il-6Cebpb Cd206Arg1Il-10Tgf-β Cd200r Cx3cr1Cd200Cx3cl1-Cx3cr1Il-1β Il-6Cd206Tgf-β

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Prenatal Immune Challenge Differentiates the Effect of Aripiprazole and Risperidone on CD200–CD200R and CX3CL1–CX3CR1 Dyads and Microglial Polarization: A Study in Organotypic Cortical Cultures

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