Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization

Abstract

An interaction between external stressors and intrinsic vulnerability is one of the longest standing pathoaetiological explanations for schizophrenia. However, novel lines of evidence from genetics, preclinical studies, epidemiology and imaging have shed new light on the mechanisms that may underlie this, implicating microglia as a key potential mediator. Microglia are the primary immune cells of the central nervous system. They have a central role in the inflammatory response, and are also involved in synaptic pruning and neuronal remodeling. In addition to immune and traumatic stimuli, microglial activation occurs in response to psychosocial stress. Activation of microglia perinatally may make them vulnerable to subsequent overactivation by stressors experienced in later life. Recent advances in genetics have shown that variations in the complement system are associated with schizophrenia, and this system has been shown to regulate microglial synaptic pruning. This suggests a mechanism via which genetic and environmental influences may act synergistically and lead to pathological microglial activation. Microglial overactivation may lead to excessive synaptic pruning and loss of cortical gray matter. Microglial mediated damage to stress-sensitive regions such as the prefrontal cortex and hippocampus may lead directly to cognitive and negative symptoms, and account for a number of the structural brain changes associated with the disorder. Loss of cortical control may also lead to disinhibition of subcortical dopamine—thereby leading to positive psychotic symptoms. We review the preclinical and in vivo evidence for this model and consider the implications this has for treatment, and future directions.

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

“…In the brain, these signaling molecules are mainly released by microglia and astrocytes, which have key roles in the immune response (9). Therefore, increases in numbers or activity of these cells in schizophrenia have been hypothesized (48,49). In postmortem studies, higher levels of brain glial cell markers, such as human leukocyte antigenantigen D related and CD11b, have been observed in patients, although results have been mixed (50)(51)(52).…”

A within‐subject consideration of the psychotic spectrum disorder concept in a patient in remission associated with cortical gray matter recovery

“…Bipolar patients, in general, manifest less gray matter loss compared to normal controls, than do schizophrenia patients, with loss concentrated in cingulate cortical areas . Gray matter loss in schizophrenia and bipolar disorder has been attributed to excessive pruning and inflammation during early development, as well as during the prodromal period, with genetic factors and stress considered to be the major basis for the loss of gray matter . Longitudinal MRI studies indicate progressive loss of brain volume in some patients with schizophrenia or bipolar disorder .…”

“…47 Gray matter loss in schizophrenia and bipolar disorder has been attributed to excessive pruning and inflammation during early development, as well as during the prodromal period, with genetic factors and stress considered to be the major basis for the loss of gray matter. [48][49][50] Longitudinal MRI studies indicate progressive loss of brain volume in some patients with schizophrenia or bipolar disorder. 51,52 On the other hand, the possibility that drug treatment, particularly APDs, may be the cause of gray matter loss, has been extensively investigated with some concluding that there is a dose-related reduction of gray matter due to APDs.…”

PET studies of the glial cell marker TSPO in psychosis patients - a meta-analysis using individual participant data

“…In the brain, these signaling molecules are mainly released by microglia and astrocytes, which have key roles in the immune response (9). Therefore, increases in numbers or activity of these cells in schizophrenia has been hypothesized (48,49). In post-mortem studies, increases in brain glial cell markers such as HLA-DR and CD11b have been observed in patients, although results have been mixed (50)(51)(52).…”