Elsevier

Neurobiology of Disease

Volume 99, March 2017, Pages 58-65
Neurobiology of Disease

Review
Role of microglia disturbances and immune-related marker abnormalities in cortical circuitry dysfunction in schizophrenia

https://doi.org/10.1016/j.nbd.2016.12.019Get rights and content

Abstract

Studies of genetics, serum cytokines, and autoimmune illnesses suggest that immune-related abnormalities are involved in the disease process of schizophrenia. Furthermore, direct evidence of cortical immune activation, including markedly elevated levels of many immune-related markers, have been reported in the prefrontal cortex in multiple cohorts of schizophrenia subjects. Within the prefrontal cortex in schizophrenia, deficits in the basilar dendritic spines of layer 3 pyramidal neurons and disturbances in inhibitory inputs to pyramidal neurons have also been commonly reported. Interestingly, microglia, the resident immune-related cells of the brain, also regulate excitatory and inhibitory input to pyramidal neurons. Consequently, in this review, we describe the cytological and molecular evidence of immune activation that has been reported in the brains of individuals with schizophrenia and the potential links between these immune-related disturbances with previously reported disturbances in pyramidal and inhibitory neurons in the disorder. Finally, we discuss the role that activated microglia may play in connecting these observations and as potential therapeutic treatment targets in schizophrenia.

Introduction

Multiple lines of evidence from biomarker, genetic and epidemiological studies have converged to indicate an important role of immune-related abnormalities in the disease process of schizophrenia (Horvath and Mirnics, 2014). For example, higher levels of proinflammatory cytokines have been consistently reported in the peripheral serum of individuals with schizophrenia (Goldsmith et al., 2016, Miller et al., 2011, Potvin et al., 2008). Furthermore, variants in immune-related genes that associate with a higher risk for schizophrenia have been identified across multiple, large scale genome-wide association studies (Purcell et al., 2009, Ripke et al., 2011, Shi et al., 2009, Stefansson et al., 2009). In addition, individuals with schizophrenia have a higher rate of autoimmune illnesses, and individuals with autoimmune illness have a higher frequency of psychotic symptoms (Benros et al., 2014a, Benros et al., 2014b). Prenatal exposure to maternal immune activation, such as maternal exposure to infectious disease during pregnancy, is also associated with a higher risk of offspring developing schizophrenia later in life (Brown and Derkits, 2010). Recent studies have also reported direct evidence of marked elevations in transcript levels for multiple immune-related markers, including proinflammatory cytokines, in the prefrontal cortex of individuals with schizophrenia (Fillman et al., 2013, Volk et al., 2015).

Immune-related disturbances may be directly involved in the pathophysiology of cortical circuitry dysfunction in the illness. Deficits in basilar dendritic spines of deep layer 3 pyramidal neurons, a primary source of excitatory input, have been reported in the prefrontal cortex in schizophrenia (Glantz and Lewis, 2000, Konopaske et al., 2014). In addition, alterations in the CDC42 and ARP2/3 pathways, which regulate the actin cytoskeleton within dendritic spines, have been reported in pyramidal neurons in the prefrontal cortex in schizophrenia (Datta et al., 2015, Hill et al., 2006, Ide and Lewis, 2010). Furthermore, disturbances in inhibitory neurons have been consistently reported in the prefrontal cortex across large cohorts of schizophrenia subjects, including deficits in transcript levels for the GABA synthesizing enzyme glutamate decarboxylase (GAD67) (Akbarian et al., 1995, Curley et al., 2011, Duncan et al., 2010, Guidotti et al., 2000, Straub et al., 2007, Volk et al., 2000). In addition, lower mRNA levels for the calcium-binding protein parvalbumin, which is expressed by a distinct neuronal population that provides perisomatic inhibitory input to pyramidal neurons, have also been widely replicated in the prefrontal cortex in schizophrenia (Fung et al., 2010, Hashimoto et al., 2003, Mellios et al., 2009, Volk et al., 2012). Interestingly, recent evidence has found that microglia, the resident immune-related cells located in brain parenchyma, regulate excitatory inputs to spines and inhibitory inputs to the soma of pyramidal neurons (Chen et al., 2014, Paolicelli et al., 2011, Schafer et al., 2012, Sekar et al., 2016, Stevens et al., 2007, Trapp et al., 2007, Tremblay et al., 2010, Wake et al., 2009). Thus, activated microglia may represent a central node that connects the findings of cortical immune activation with disturbances in excitatory and inhibitory inputs to cortical pyramidal neurons.

Consequently, this review describes the peripheral serum, genetic and epidemiological evidence linking immune system abnormalities to schizophrenia. Cellular and molecular evidence of cortical immune activation and its potential impact on cortical circuitry function in schizophrenia are also discussed. Evidence that activated microglia may impact pyramidal neuron dendritic spine density and inhibitory neuron function in schizophrenia is presented as well. Finally, ideas for future directions for investigating the role of activated microglia in cortical circuitry dysfunction in schizophrenia, and the potential impact on discovering novel treatment targets, are presented.

Section snippets

Peripheral serum and cerebrospinal fluid evidence of immune activation in schizophrenia

Multiple meta-analyses have confirmed the presence of higher cytokine levels in the peripheral serum of individuals with schizophrenia (Goldsmith et al., 2016, Miller et al., 2011, Potvin et al., 2008). Serum levels of proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α have been reported to be elevated in individuals at all stages of the illness including first episode psychosis, acute relapse, and later in life (Goldsmith et al., 2016, Miller et al., 2011). Furthermore, a

Molecular indicators of cortical immune activation in schizophrenia

Evidence of immune activation in the brain has also been reported in schizophrenia, particularly at the transcriptome level. For example, two early microarray studies identified immune-related mRNAs as being some of the most highly over-expressed mRNAs in the prefrontal cortex in schizophrenia (Arion et al., 2007, Saetre et al., 2007). In particular, transcripts for interferon-induced transmembrane protein (IFITM), which serves as a viral restriction factor that inhibits the replication of a

4. Evidence of microglia disturbances in schizophrenia

The presence of cortical immune activation in the disorder may indicate the involvement of microglia, the resident immune-related cells of the central nervous system. Indeed, variants of microglia-related genes (e.g., C4 (Sekar et al., 2016), CUB and Sushi multiple domains-1 [CSMD1] (Havik et al., 2011, Ripke et al., 2011, Schizophrenia Working Group of the Psychiatric Genomics Con)) have been recently associated with a higher risk for developing schizophrenia in GWAS studies, as described

5. The potential role of activated microglia in cortical circuitry dysfunction in schizophrenia

Microglia may play an important role in the cortical circuitry disturbances reported in schizophrenia, such as deficits in the basilar dendritic spines of deep layer 3 pyramidal neurons in the prefrontal cortex (Glantz and Lewis, 2000, Konopaske et al., 2014). For example, microglial processes dynamically and preferentially interact with the dendritic spines of pyramidal neurons (Paolicelli et al., 2011, Tremblay et al., 2010, Wake et al., 2009). Furthermore, the processes of microglia that

6. Future directions

Further investigation into the contributory role of activated microglia in cortical circuitry dysfunction in schizophrenia requires addressing several additional critical questions. First, do microglia in schizophrenia have the molecular and morphological features that enable higher levels of cellular activity and spine consumption? As described earlier, existing studies of microglia in schizophrenia have generally been limited to 1) PET imaging studies that have targeted only one molecular

Acknowledgements

This work was supported by the National Institutes of Health (R01 MH100066).

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