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

• Published in: Life (Basel, Switzerland) Switzerland), 2024-06, Vol.14 (6), p.721
• Main Authors: Chamera, Katarzyna, Curzytek, Katarzyna, Kamińska, Kinga, Leśkiewicz, Monika, Basta-Kaim, Agnieszka
• Format: Article
• Language: English
• Subjects: Antipsychotics; Aripiprazole; CD200 antigen; CD40 antigen; Cell activation; Cellular control mechanisms; Central nervous system; Chemokine receptors; Chemokines; Crosstalk; CX3CR1 protein; Cytokines; Development and progression; Dopamine; Drug development; Drug interaction; Drug therapy; Drugs; E coli; Gene expression; Glucose; Health aspects; Histamine; Homeostasis; IL-1β; Immune response; Immune system; Immunosuppressive agents; Inflammation; Interleukin 10; Interleukin 6; Laboratory animals; lipopolysaccharide; Lipopolysaccharides; maternal immune activation; Membrane proteins; Mental disorders; Microglia; mRNA; Neurons; Offspring; organotypic cortical cultures; Penicillin; Physiological aspects; Polarization; Pregnant women; Psychiatric research; Psychotropic drugs; Risperidone; Schizophrenia; Surveys; Transforming growth factor-b
• ISSN: 2075-1729; 2075-1729
• DOI: 10.3390/life14060721

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 the and axes, 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 of and affected the OCCs' response to additional LPS exposure in terms of this parameter. LPS downregulated the expression and profoundly changed the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Risperidone increased expression in MIA OCCs, while aripiprazole treatment elevated the gene levels of the dyad 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.