Abstract
Maternal inflammation during pregnancy causes later-in-life alterations of the offspring’s brain structure and function. These abnormalities increase the risk of developing several psychiatric and neurological disorders, including schizophrenia, intellectual disability, bipolar disorder, autism spectrum disorder, microcephaly, and cerebral palsy. Here, we discuss how astrocytes might contribute to postnatal brain dysfunction following maternal inflammation, focusing on the signaling mediated by two families of plasma membrane channels: hemi-channels and pannexons. [Ca2+]i imbalance linked to the opening of astrocytic hemichannels and pannexons could disturb essential functions that sustain astrocytic survival and astrocyte-to-neuron support, including energy and redox homeostasis, uptake of K+ and glutamate, and the delivery of neurotrophic factors and energy-rich metabolites. Both phenomena could make neurons more susceptible to the harmful effect of prenatal inflammation and the experience of a second immune challenge during adulthood. On the other hand, maternal inflammation could cause excitotoxicity by producing the release of high amounts of gliotransmitters via astrocytic hemichannels/pannexons, eliciting further neuronal damage. Understanding how hemichannels and pannexons participate in maternal inflammation-induced brain abnormalities could be critical for developing pharmacological therapies against neurological disorders observed in the offspring.
Highlights
Clinical evidence has established that environmental clues acting at specific windows during fetal development affect lifelong trajectories across health and disease [1]
These processes begin with the extracellular influx of Ca2+ via ion channels and through Ca2+ release from intracellular stores, causing [Ca2+]i transients that vary in frequency, kinetic and spatial spread according to the astrocyte anatomical zone [61]
The notion of the brain being a privileged organ with a poor immune capacity does not conciliate with recent evidence indicating that it performs complex immune responses primarily based on its innate immune system, a “first line” of defense ensuring brain homeostasis [225,226,227]
Summary
Clinical evidence has established that environmental clues acting at specific windows during fetal development affect lifelong trajectories across health and disease [1]. Maternal immune perturbations during pregnancy, either in response to infections or noninfectious stimuli (e.g., diabetes, stress, maternal allergic asthma, obesity, or toxin exposures), cause enduring or later-in-life alterations of the offspring brain structure and function [4] The latter increases the risk of developing several psychiatric and neurological disorders, including schizophrenia, intellectual disability, bipolar disorder, autism spectrum disorder (ASD), microcephaly, and cerebral palsy [5] (Figure 1). There is a certain consensus that a common pathogenic pathway linked to cytokinemediated inflammation disrupts fetal brain development and adult central nervous system (CNS) maturation following maternal disease [4,30,31] Coherent with this notion, human epidemiological evidence indicates that high gestational levels of IL-1α, IL-6, IL-8, IFN-γ, TNF-α, granulocyte macrophage colony-stimulating factor, and C-reactive protein augment the incidence of schizophrenia and ASD in the progeny [32,33,34] (Figure 1). Multiple neurological disorders associate with prenatal inflammation: schizophrenia, autism spectrum disorder, bipolar disorder, and cerebral palsy
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