Microglia-neuron interactions in schizophrenia

Abstract

Multiple lines of evidence implicate increased neuroinflammation mediated by glial cells to play a key role in neurodevelopmental disorders such as schizophrenia. Microglia, which are the primary innate immune cells of the brain, are crucial for the refinement of the synaptic circuitry during early brain development by synaptic pruning and the regulation of synaptic plasticity during adulthood. Schizophrenia risk factors as genetics or environmental influences may further be linked to increased activation of microglia, an increase of pro-inflammatory cytokine levels and activation of the inflammasome resulting in an overall elevated neuroinflammatory state in patients. Synaptic loss, one of the central pathological hallmarks of schizophrenia, is believed to be due to excess removal of synapses by activated microglia, primarily affecting glutamatergic neurons. Therefore, it is crucial to investigate microglia-neuron interactions, which has been done by multiple studies focusing on post-mortem brain tissues, brain imaging, animal models and patient iPSC-derived 2D culture systems. In this review, we summarize the major findings in patients and in vivo and in vitro models in the context of neuron-microglia interactions in schizophrenia and secondly discuss the potential of anti-inflammatory treatments for the alleviation of positive, negative, and cognitive symptoms.

Keywords: co-culture; complement system; inflammation; microglia; neuron; schizophrenia; synaptic pruning.

FIGURE 1

Summarization of the previously described findings implicating aberrant synaptic pruning by activated microglia in SCZ. Under SCZ conditions, microglia depict an activated state morphologically and functionally by the release of pro-inflammatory cytokines such as IL-6, TNF-α, IFN-γ. Activated microglia show increased engulfment of synapses and spines of cortical pyramidal neurons resulting in reduced synaptic density. Increased expression of the complement protein C4A in SCZ neuronal structures is assumed to be responsible for the excessive removal of synapses via the complement system. Anti-inflammatory treatment such as minocycline suppresses the activated microglial phenotype and can lead to reduced uptake of synaptic structures. Created with BioRender.com.