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Through “gliotransmitter” release, ACs may be integral to various neural systems, such as the coincidence detection system that is significant for plasticity and map formation in the hippocampus (Min and Nevian, 2012). Similarly, it has been shown that ACs are essential to synaptic function in the hippocampus, regulating long term potentiation (LTP) by supplying lactate produced from glycogen stored in ACs (Suzuki et al. 2011). This highlights how ACs can have a direct impact on neuronal functions.
Further evidence of the involvement of ACs in schizophrenia comes from the fact that expression of catechol-O-methyltransferase (COMT) signalling is increased in ACs but not in COMT-expressing neurons in schizophrenic patients and importantly, this effect appears independent of medication used (Brisch et al. 2009). As COMT is responsible for the breakdown of catecholamines including dopamine, this work points to involvement of ACs in dopamine signalling and monoamine metabolism. Earlier work by Owen et al. (1987) supports this, having found reduced concentrations of monoamine oxidase B (MAO-B), another enzyme responsible for dopamine breakdown, in the frontal and temporal cortices of schizophrenic patients.
Additionally, Toxoplasmosis gondii is known to activate ACs and stimulate synthesis of kynurenic acid (Schwarcz and Hunter, 2007), and as T. gondii infection is a risk factor for schizophrenia (Torrey et al. 2007) this indicates that ACs could mediate the increased disease risk due to the environmental factor through the kynurenic acid pathway. This shows how glial cells may underlie the risk posed by various environmental factors. It is possible that ACs become hypersensitive following a prenatal or perinatal infection, such that they then elicit an exaggerated response later in development, and this may be causal or contributory to schizophrenia development (Takahashi and Sakurai, 2013).
Overall, several studies indicate that ACs are a contributing factor in the dysregulation of glutamatergic and dopaminergic signalling in schizophrenia. Most typical and atypical antipsychotics agents act positively on schizophrenia-associated disrupted AC metabolism, through interactions with their dopamine receptor (Bernstein et al. 2015). Lithium may have utility for increasing glutamine synthetase levels (Kalkman, 2011), however the potential of many other “gliotransmitters” has not been fully investigated. Clozapine has been found to enhance release of D-serine from ACs in hippocampal cultures (Tanahashi et al. 2012) and ACs are significant for the immune regulation of the central nervous system (CNS) through their expression of major histocompatibility complex (MHC) II antigens and production of cytokines, including interleukin-1 (IL-1), tumour necrosis factor (TNF-) and IL-6 (Norris and Benveniste, 1993). Several immune-related therapeutic concepts have been posited, including combination therapy with anti-inflammatory agents such as COX-2 inhibitors (Müller et al. 2012).
The immune hypothesis of schizophrenia is a more recent proposal surrounding the pathogenesis and pathophysiology of schizophrenia, and as microglial cells are the immune mediators of the CNS, they are central to this hypothesis. The onset of schizophrenia in early adulthood with both progressive and benign courses (see Figure 3) is similar to the disease courses of autoimmune disorders (Steiner et al. 2012), and immunity and inflammation represent an important risk factor for development of psychosis (Bergink et al. 2014).
In terms of the immune hypothesis, genetic analysis has found an association with the HLA gene (responsible for the MHC gene product) and schizophrenia, as well as polymorphisms of IL-1, IL-2 and IL-4 as significantly associated with schizophrenia (Lencz et al. 2007). Environmentally, there has been an association identified between schizophrenia and infections, such as influenza during pregnancy, cytomegalovirus and herpes virus (Yolken and Torrey, 2008), which could trigger autoimmune disease through molecular mimicry. Epidemiological work has shown that severe infections requiring treatment and development of autoimmune diseases like psoriasis are risk factors for development of schizophrenia and schizophrenia-spectrum disorders (Benros et al. 2011). Regarding cytokines, Miller et al. (2011) found increased levels of IL-12, IFN- and TNF- in schizophrenic patients during acute exacerbations of symptoms.
Interestingly, the GWAS performed by Goudriaan et al. (2014) did not find any association between microglial gene sets and schizophrenia, highlighting the importance of environmental factors in the immune-related pathogenesis of schizophrenia. However, gene expression profiling studies did find involvement of monocytes, monocytosis and the mononuclear phagocyte system (MPS) in schizophrenia (Drexhage et al. 2010). Microglial cells are the MPS cells of the brain, responsible for phagocytosis as well as regulating the immune responses in the brain, alongside ACs (Takahashi and Sakurai, 2013). Physiologically, microglia are essential for phagocytosis in programmed cell death during embryonal development, as well as synaptic pruning and axonal remodelling (Trembley and Majewska, 2011, Beumer et al. 2012). Microglia regulate synaptic structure, indicating a potential role for microglia dysfunction in the abnormal synaptic wiring found in schizophrenia (Faludi and Mirnics, 2011).
Microglial activation in schizophrenia has been indicated by post-mortem and positron emission tomography (PET) studies analysing microglial markers such as MHC II, CD40 and CD68 (Takahashi and Sakurai, 2013). A strong schizophrenia-related HLA-DR expression has been found in the hippocampus and prefrontal cortex (Bayer et al. 1999). It has even been suggested that microglial activation associates with suicidality, based on two studies analysing HLA-DR-immmunoreactive microglial cells in the mediodorsal thalamus, prefrontal and anterior cingulate cortex (Steiner et al. 2008). Microglial activation even appears to scale with the severity of disease, with a stronger association of HLA-DR-immunoreactive microglial cells in patients with paranoid schizophrenia presenting with more prominent psychotic positive symptoms, compared to patients with residual schizophrenia presenting with more prominent negative symptoms (Takahashi and Sakurai, 2013).
Fillman et al. (2013) performed a large post-mortem study to find 798 differentially regulated transcripts in schizophrenia. This included a correlation of HLA-DP/DQ/DR expression with IL-1 expression – reinforcing the hypothesised link between MPS activation and increased pro-inflammatory cytokine production in schizophrenic brains. However, post-mortem studies might not reflect normal pathophysiology of the disease if the individual died during a stable disease phase. Therefore real-time, in vivo PET imaging could offer a better method for analysis, showing local and specific immune activation, for example in the hippocampus during a psychosis (Doorduin et al. 2008).
Microglial cells function closely with ACs, so can also influence neurotransmission. Work has shown that secreted IL-1 and IL-2 are capable of modulating catecholamine levels (Labuzek et al. 2005). Microglia have also been shown to modulate dopaminergic neuronal cell growth and death following inflammation (Saijo and Glass, 2011). Interestingly, while administered systemically as cancer therapy, IL-2 can induce transient psychotic episodes, depression and even suicidality in rare cases (Walker et al. 1997).
The immune hypothesis of schizophrenia and microglial cells highlights the potential for anti-inflammatory therapy in treatment of schizophrenia, including compounds already in use for other conditions, such as etanercept, a TNF- antagonist. Mentioned previously, the tetracycline antibiotic minocycline suppresses the release of pro-inflammatory molecules from microglial cells such as IL-1, NO and TNF-, by blocking the nuclear translocation of NFkB of activated B-cells (Lai and Todd, 2006), and studies have already shown the potential benefits in schizophrenia (Chaudhry et al. 2012). COX-2 inhibitors also have potential, as COX-2 is increased in MPS cells. COX-2 inhibition could be an effective adjunctive therapy (Akhondzadeh et al. 2007) however efficacy has only been shown so far in patients who have recently developed the disease, highlighting the importance of disease progression in identifying effective treatments (see Figure 2).
Overall, several growing bodies of evidence can now show a clear link between glial cells and pathogenesis and pathophysiology of schizophrenia. This new “glial perspective” on schizophrenia may offer a way to deeper understand the disease and how to treat it. Oligodendrocytes, astrocytes and microglia have critical involvement in the white matter tract abnormalities, neurotransmission abnormalities, immune and inflammatory processes that underlie pathology in schizophrenia. Therefore it would appear that the evidence clearly justifies the need to work towards understanding these processes further to help develop new treatments or adjunctive therapy for schizophrenia, with better efficacy than current treatment options and less adverse side effects – in aid of enhancing treatment for one of the most debilitating of the neuropsychiatric disorders.
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