Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

Abstract

Maternal infections during pregnancy increase the risk for schizophrenia and related disorders of putative neurodevelopmental origin in the offspring. This association has been attributed to enhanced expression of pro-inflammatory cytokines in the fetal environment in response to maternal immunological stimulation. In contrast, the specific roles of anti-inflammatory cytokines are virtually unknown in this context. Here, we demonstrate that genetically enforced expression of the anti-inflammatory cytokine interleukin (IL)-10 by macrophages attenuates the long-term behavioral and pharmacological consequences of prenatal immune activation in a mouse model of prenatal viral-like infection by polyriboinosinic-polyribocytidilic acid (PolyI:C; 2 mg/kg, intravenously). In the absence of a discrete prenatal inflammatory stimulus, however, enhanced levels of IL-10 at the maternal-fetal interface by itself also precipitates specific behavioral abnormalities in the grown offspring. This highlights that in addition to the disruptive effects of excess pro-inflammatory molecules, a shift toward enhanced antiinflammatory signaling in prenatal life can similarly affect cognitive and behavioral development. Hence, shifts of the balance between pro-and anti-inflammatory cytokine classes may be a critical determinant of the final impact on neurodevelopment following early life infection or innate immune imbalances.

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

“…CX43 expression was correlated inversely with cell proliferation activity during postnatal development (Miragall et al 1996). Activated microglial cells release cytokines like IL-Iβ, and TNF-α and downregulate CX43 in cultures of astrocytes exposed to bacterial lipoplysaccarides (Meme et al 2006). Finally, mice with astrocyte-directed inactivation of CX43 exhibit increased exploratory behavior, impaired motor capacities, and change in brain acetylcholine levels (Frisch et al 2003).…”

The Role of the Immune System in Autism Spectrum Disorder

“…Choi et al (2016) also showed that their MIA model induced the production of several other cytokines, finding increased levels of TNF-α, IFN-β, and IL-1β 3 h following MIA induction, but not the anti-inflammatory IL-10. A poly(I:C) MIA model by Meyer et al (2008) suggested that maternal IL-10 may be able to attenuate behavioral and pharmacological dysfunctions.…”

“…However, it should be considered that there might be a combination of these three pathways. Maternal inflammation history and the pro-inflammatory/anti-inflammatory cytokine balance are thus particularly important avenues for further study, especially at the interface between mother and fetus (Meyer et al, 2008;Jones and Thomsen, 2013;Young et al, 2016).…”

Joint Effects of Exposure to Prenatal Infection and Peripubertal Psychological Trauma in Schizophrenia

“…One prevalent hypothesis suggests that a common pathogenic mechanism involving increased production of cytokines and other mediators of inflammation mediates the link between prenatal infection and subsequent risk of schizophrenia. 8,9 Epidemiological support for this hypothesis, however, remains controversial, 10,11 suggesting furthermore that other mediating factors may play a role as well. 12 Exposure to traumatizing events during postnatal development is another environmental insult that has received broad recognition in the etiology of neurodevelopmental disorders.…”