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Review
.2020 Aug 27:14:274.
doi: 10.3389/fncel.2020.00274. eCollection 2020.

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

Affiliations
Review

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

Ashley L Comer et al. Front Cell Neurosci..

Abstract

Schizophrenia is a disorder with a heterogeneous etiology involving complex interplay between genetic and environmental risk factors. The immune system is now known to play vital roles in nervous system function and pathology through regulating neuronal and glial development, synaptic plasticity, and behavior. In this regard, the immune system is positioned as a common link between the seemingly diverse genetic and environmental risk factors for schizophrenia. Synthesizing information about how the immune-brain axis is affected by multiple factors and how these factors might interact in schizophrenia is necessary to better understand the pathogenesis of this disease. Such knowledge will aid in the development of more translatable animal models that may lead to effective therapeutic interventions. Here, we provide an overview of the genetic risk factors for schizophrenia that modulate immune function. We also explore environmental factors for schizophrenia including exposure to pollution, gut dysbiosis, maternal immune activation and early-life stress, and how the consequences of these risk factors are linked to microglial function and dysfunction. We also propose that morphological and signaling deficits of the blood-brain barrier, as observed in some individuals with schizophrenia, can act as a gateway between peripheral and central nervous system inflammation, thus affecting microglia in their essential functions. Finally, we describe the diverse roles that microglia play in response to neuroinflammation and their impact on brain development and homeostasis, as well as schizophrenia pathophysiology.

Keywords: Environment; brain development; genes; microglia; neurodevelopmental; neuroinflammation; risk factors; schizophrenia.

Copyright © 2020 Comer, Carrier, Tremblay and Cruz-Martín.

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Figures

FIGURE 1
FIGURE 1
Overlap between immune-signaling genes that are associated with pollution and SCZ. Of the immune genes that are associated with SCZ, many are also found to be altered either in humans or animals exposed to pollutants, offering a genetic point of convergence between changes in pollution-mediated inflammatory signaling and SCZ. Inflammatory gene expression, including TLR2, TNF-α, MHC, CRP, TLR4, IRF3, complement pathway, IL-6, IFN-y, CD14, IL-10, TGF-β are altered in SCZ, while TNF-α, TLR4, IL-6, CD14 and IL-1 are altered in SCZ and after exposure to air pollution. These genes are specifically enriched in microglia.
FIGURE 2
FIGURE 2
Key components of the microglial sensome associated with SCZ. The microglial sensome is a group of receptors and proteins that allow microglia to sense and respond to their changing environment, facilitating the diverse roles of microglial as well as their complex interactions with multiple cell-types in the brain. Components of the microglia sensome can be categorized to include purinergic, cytokine, Fc, pattern recognition, extracellular matrix, and cell-cell interaction receptors and ligands, among others not listed here. Future work could aim at targeting the microglial sensome to normalize microglial function in SCZ.
FIGURE 3
FIGURE 3
Neuroinflammation-induced changes in microglia that are implicated in SCZ pathogenicity. Risk factors for SCZ that alter microglial function and enhance neuroinflammation include pollution, stress, nutrition induced gut-brain axis dysbiosis, viral infection, maternal immune activation, genetic predisposition, and cytokine secretion. Homeostatic microglia perform their immune sentinel role by interacting with neurons to guide circuit wiring during development. In an increased inflammatory milieu, loss of microglial homeostasis perturbs microglia-neuron interactions that may cause altered plasticity due to pathogenic synaptic formation, synaptic stripping, and pruning. Therapeutic approaches that promote homeostatic microglia through the reduction of neuroinflammation via anti-inflammatory drugs, microglial inhibition and repopulation, improved nutrition, environmental enrichment, and prevention of psychological stress could be potentially exploited to limit exacerbation of SCZ.
FIGURE 4
FIGURE 4
Neuroinflammation-induced dysfunctions that alter glutamatergic transmission in SCZ. Changes in glutamatergic transmission are known to occur in SCZ. Neuroinflammation impacts excitatory circuitry in SCZ through complement-mediated engulfment of excitatory synapses, the production of autoantibodies against NMDARs, changes in glutamate homeostasis potentially mediated by alterations in astrocytes and changes in the gut-brain axis, a known regulator of glutamate synthesis that is able to impact CNS functions such as stress responses. These changes in excitatory transmission can alter brain circuitry, for example, by altering synaptic plasticity and long-range excitation.
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