Microglial Activation and Psychotic Disorders: Evidence from Pre-clinical and Clinical Studies

Abstract

Clinical and pre-clinical studies have demonstrated an important role of neuroinflammation in the etiology of schizophrenia. While the underlying mechanisms remain poorly understood, there are some studies demonstrating an association between maternal immune activation and behavioral changes in adult offspring and identifying early life infection as a trigger for schizophrenia; in addition, inflammatory markers were found to be increased in the schizophrenic post-mortem brain. During maternal immune activation, pro-inflammatory mediators such as cytokines, chemokines, antibodies, and acute-phase proteins are released in the maternal bloodstream, thus increasing the permeability of the placental barrier and the fetal blood-brain barrier, allowing the inflammatory mediators to enter the fetal brain. In the central nervous system (CNS), these pro-inflammatory mediators are able to activate microglial cells that can release pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6. As a consequence, circulating immune cells may infiltrate the brain, increasing cytokine levels and releasing antibodies that aggravate the neuroinflammation. Neuroinflammation may affect processes that are pivotal for normal brain maturation such as myelination, synaptic pruning, and neuronal remodeling. Microglial cell activation and pro-inflammatory mediators have been extensively studied in schizophrenic post-mortem brain samples. Some results of these investigations demonstrated an increase in microglial activation markers, cytokines, and chemokines in post-mortem brain samples from individuals with schizophrenia. In contrast, there are studies that have demonstrated low levels of microglial activation makers in the schizophrenic post-mortem brain. Thus, based on the important role of neuroinflammation as a trigger in the development of schizophrenia, this chapter aims (1) to enumerate evidence of neuroinflammation and microglial activation from pre-clinical schizophrenia models, (2) to show links between schizophrenia and neuroinflammation in clinical studies, and (3) to identify mechanisms by which microglial activation may influence in the development of schizophrenia.

Keywords: Microglia; Neuroinflammation; Psychosis; Schizophrenia; Schizophrenia-like behavior.