The Outcomes of Maternal Immune Activation Induced with the Viral Mimetic Poly I:C on Microglia in Exposed Rodent Offspring

Abstract

Maternal immune activation (MIA) can result from a variety of maternal inflammatory factors, including metabolic disorders, nutritional deficits, infections, and psychosocial stress. MIA has been consistently recognized as a major risk factor for neurodevelopmental disorders, and this association seems to be especially important for viral infections, as viral exposure during pregnancy was associated with a higher risk of developing neurodevelopmental disorders, such as schizophrenia. In MIA, the gestational parent’s inflammatory response to an immune stimulus alters or interrupts fetal development, triggering neurodevelopmental consequences. As MIA can occur in any pregnancy it is important to understand the many factors at play that contribute to altered brain development in the offspring, especially considering recent global events such as the COVID-19 pandemic. The underlying mechanisms by which MIA results in deleterious outcomes are not yet clear, but due to the inflammatory response it initiates, it is becoming apparent that microglia are critically involved. Through investigation of MIA animal models, the role of microglia in this field is becoming more evident. Compelling evidence from animal models indicates that MIA can disrupt synaptic pruning, neuronal progenitor cell proliferation /differentiation, oligodendrogenesis and more. Microglia appear as an active player, assisting these neural-related functions during healthy development, but also mediating MIA-induced disturbances in these critical processes when neurodevelopment is challenged. The present review illustrates this complex web by reviewing recent literature, focusing on the outcomes of MIA resulting from viral mimetic poly I:C in rodents, to provide a clear description of how MIA impacts microglial functions and what this means for the offspring’s neurodevelopment. Moreover, we discuss the possible implications of the COVID-19 pandemic on the neurodevelopment of the current and next generations in the frame of MIA models and propose some putative pharmacological and non-pharmacological approaches to prevent or attenuate MIA consequences.

Modeling the neuroimmune system in Alzheimer’s and Parkinson’s diseases

“…As stated in Sect. 2.2.1, although Aβ plaques are the central cause of the synapse loss and cognitive deficit in AD, chronic inflammation has also been implicated in the onset and progression of these AD-related pathologies [ 200 , 201 ]. Novel techniques were designed to understand the role of exacerbated inflammation, by using a viral mimetic polyinosinic:polycytidylic acid (poly I:C).…”

“…Novel techniques were designed to understand the role of exacerbated inflammation, by using a viral mimetic polyinosinic:polycytidylic acid (poly I:C). The poly I:C model is known to achieve an increased Aβ deposition and cognitive deficits in a non-transgenic mouse [ 200 , 201 ]. Additionally, several genetic variants of TREM2 (R47H and R62H) have been associated with an increased risk of developing sporadic AD and are being studied in the AD context [ 202 ].…”

Inhibition of NKCC1 Ameliorates Anxiety and Autistic Behaviors Induced by Maternal Immune Activation in Mice

“…Importantly, injection of the RNA virus analogue poly(I:C) into pregnant mice results in behavioral and histological abnormalities in MIA offspring [ 22 , 23 , 24 ]. Previous studies have shown that prenatal poly(I:C) exposure leads to microglia activation in offspring [ 25 , 26 , 27 ]. However, it remains unknown as to how maternal immune activation by pregnancy infection disrupts offspring brain development and function.…”

PolyI:C Maternal Immune Activation on E9.5 Causes the Deregulation of Microglia and the Complement System in Mice, Leading to Decreased Synaptic Spine Density

“…The brain's resident immune cells, microglia, are key players in neurodevelopment, and may act as an important link between immune dysregulation in MIA and neurological outcomes [13]. Microglia populate the brain early in development (E9.5) and are replaced slowly, so early perturbations may carry forward [14][15][16].…”

“…Microglia populate the brain early in development (E9.5) and are replaced slowly, so early perturbations may carry forward [14][15][16]. In addition to supporting neuronal proliferation and survival [13], microglia play a key role in synaptic development through "pruning" synapses by mechanisms such as phagocytosis and trogocytosis [17][18][19]. Dysfunction in synaptic transmission is a key feature of schizophrenia and ASD, and MIA models recapitulate alterations in synaptic spine density; although, whether density is increased or decreased appears to be sensitive to brain region, sex, and the MIA protocol used [20].…”