Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

Abstract

The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances.

Insights into the Potential Impact of Quetiapine on the Microglial Trajectory and Inflammatory Response in Organotypic Cortical Cultures Derived from Rat Offspring

“…In rats after basolateral amygdala lesions generated using quinolinic acid [13], as well as in a rodent model based on prenatal exposure to polyinosinic-polycytidylic acid [14], quetiapine normalized deficits in prepulse inhibition of sensorimotor gating. A similar phenomenon was reported for rat offspring subjected to lipopolysaccharide (LPS) in the prenatal period [15]. Furthermore, treatment with quetiapine attenuated behaviours resembling this neurological condition (e.g., hyperactivity, spatial working memory impairments and sensorimotor gating deficits) in MK-801-injected mice [16].…”

“…To date, data concerning the anti-inflammatory action of quetiapine have varied and depended on the experimental model used, the dose and the administration method of the drug. Previously published reports underlined a doubleedged immunomodulatory mechanism of this antipsychotic [15], which could be crucial in the context of the efficacy of quetiapine, as it was also influenced by the prior inflammatory activation state of cells [84]. Thus, the modulatory potential of quetiapine might be related to the inhibition of pro-inflammatory response rather than the stimulation of its antiinflammatory components.…”

“…Our present research was conducted in a neurodevelopmental model of schizophrenia based on the administration of bacterial endotoxin (specifically, LPS) to female rats throughout pregnancy [15,29,30,33,34,45]. MIA applied in this paradigm produces age-dependent behavioural deficits in sensorimotor gating [29,30], disturbances in exploration [33,45], spontaneous and amphetamine-induced locomotor activity [35] and social interactions [45] as well as the presence of anxiety behaviour [33].…”

“…Through binding with the cognate receptor, CD200 initiates an intracellular signalling cascade, resulting in a general inhibition of microglial pro-inflammatory marker expression and cytokine responses to immune stimuli [64]. Malfunction of CD200-CD200R communication, as well as the CX3CL1-CX3CR1 pair, another critical neuron-microglia axis, limited the resolution of inflammation, potentiated microglial pro-inflammatory activity and exacerbated disease severity and/or progression in several models of neuroinflammatory diseases [15,65,66]. Herein, we detected deficits in Cd200r and/or Cx3cr1 expression in MIA OCCs, yet we did not find significant changes in the mRNA levels of microglial markers (Cd40, Cd206, Arg1 and Cebpb) or the expression profiles of pro-(Il-1β and Il-6) and anti-inflammatory (Il-10 and Tgf-β) cytokines.…”

The Janus face of antipsychotics in glial cells: Focus on glioprotection

“…Inhibition of microglial proton currents is also involved in the anti-inflammatory effect of clozapine and does not involve serotonin receptors. 91 Moreover, in vivo studies showed that clozapine can regulate microglial activation in a model of chronic experimental autoimmune encephalomyelitis, 92 while quetiapine modulates brain inflammatory processes in adult rats prenatally exposed to lipopolysaccharide (LPS), a model of schizophrenia-like disturbances, 93 and in a transgenic mice model of Alzheimer's disease. 39 With regard to typical antipsychotics, chlorpromazine and haloperidol have been demonstrated to exert some anti-inflammatory effects in microglial cells, 90,94 also by decreasing the release of pro-inflammatory cytokines.…”