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

Oliver Howes*, Robert McCutcheon

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

144 Citations (Scopus)


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.

Original languageEnglish
Article numbere1024
JournalTranslational psychiatry
Issue number2
Publication statusPublished - 7 Feb 2017


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