An excellent post by Ron Unger with a contribution from Brian Koehler:
“…the headlines were blaring: Schizophrenia breakthrough as genetic study reveals link to brain changes! We heard that our best hope for treating “schizophrenia” is to understand it at a genetic level, and that this new breakthrough was now getting us really started on that mission, as it showed how a genetic variation could lead to the more intense pruning of brain connections which is often seen in those diagnosed with schizophrenia. We were told that this study was very important. “For the first time, the origin of schizophrenia is no longer a complete black box” was one quote. And the acting director of the National Institute of Mental Health (NIMH) described the study as “a crucial turning point in the fight against mental illness”.
Psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia, affect a significant percentage of the world population. These disorders are associated with educational difficulties, decreased productivity and reduced quality of life, but their underlying pathophysiological mechanisms are not fully elucidated. Recently, studies have suggested that psychiatric disorders could be considered as inflammatory disorders, even though the exact mechanisms underlying this association are not known. An increase in inflammatory response and oxidative stress may lead to inflammation, which in turn can stimulate microglia in the brain. Microglial activation is roused by the M1 phenotype, which is associated with an increase in interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). On the contrary, M2 phenotype is associated with a release of anti-inflammatory cytokines. Thus, it is possible that the inflammatory response from microglial activation can contribute to brain pathology, as well as influence treatment responses. This review will highlight the role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism. More specifically, the role of microglial activation and associated molecular cascades will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.
“One theory suggests that maternal immune activation during pregnancy is a risk factor for the progeny to develop schizophrenia in adulthood (Brown, 2011). The findings from preclinical studies using models of prenatal infection and maternal immune activation through polyinosinic-polycytidylic (Poly I:C) or LPS can have a negative impact on offspring brain development (Missault et al., 2014, Reisinger et al., 2015 and Wischhof et al., 2015). Van den Eynde et al. (2014) demonstrated that offspring rats born to Poly I:C had an increase in microglia accompanied by schizophrenic-like behavior. Influenza exposure during the first gestational trimester significantly increased the risk of schizophrenia in adulthood (Brown et al., 2004). Other studies showed an association between Toxoplasma gondii and early-onset schizophrenia ( Mortensen et al., 2007), and maternal genital/reproductive infections during periconception increased the risk of schizophrenia in offspring ( Babulas et al., 2006). On this vein, several models have attempted to explain how prenatal infection can increase the risk of schizophrenia. A theory suggests that the host immune response through cytokines could mediate the effects of infection ( Girgis et al., 2014). During infection the innate immune cells are also activated by endogenous constituents that are normally released from injured cells, including ATP, S100 molecules, histones and HSPs, which are known as DAMPs ( Lu et al., 2014 and Wiersinga et al., 2014). Thus, microglia can be stimulated by numerous components including DAMPs or pro-inflammatory mediators to produce cytokines, chemokine, and induce oxidative stress. This prolonged and excessive microglial response may lead to deleterious effects on neuronal plasticity and apoptosis, leading to behavioral and cognitive deficits through exogenous as well as endogenous components ( Barichello et al., 2013 and Hu et al., 2014).
Microglial activation and an increase in microglial cells in the brain of schizophrenic patients have been reported in post-mortem studies (Bayer et al., 1999 and Radewicz et al., 2000). An increase in microglial cells was also demonstrated in schizophrenic patients who had committed suicide (Steiner et al., 2008). A positron emission tomography (PET) study showed microglial activation in recent-onset schizophrenics within the first 5 years of disease (van Berckel et al., 2008). Moreover, microglial activation through Iba-1 and iNOS in the hippocampus of adult rats was observed in an animal model of schizophrenia induced during the neonatal period. This microglial activation was accompanied by prepulse inhibition (PPI) and working memory impairment that were reversed by antipsychotic clozapine treatment (Ribeiro et al., 2013). However, in the prefrontal white matter from schizophrenic patients, Iba-1 expressing microglial cells were found only in three out of 20 schizophrenia samples compared to controls (Hercher et al., 2014).
Schizophrenia is known to be associated with alterations in the immune system, such as increased cytokine levels. In a meta-analysis, IL-1β, IL-6, and TGF-β (which also has neuroprotective and anti-inflammatory effects in the CNS) were augmented during an acute relapse in patients and in the first-episode of psychosis. These alterations in cytokines were normalized with antipsychotic treatment (Miller et al., 2011). Another meta-analysis revealed a link between polymorphism in the IL-1β gene and abnormal white and gray matter volume in schizophrenia (Najjar and Pearlman, 2015).
Schizophrenic patients have also shown DAMPs in the serum or in the cerebrospinal fluid (CSF). Micromolar concentrations of S100B protein (a protein involved with cell cycle progression and differentiation) can induce apoptosis in neurons and astrocytes in response to the activation of the advanced glycation end-products receptor (RAGE) (Steiner et al., 2009). S100B protein has been shown to be augmented in the serum and in the CSF of untreated schizophrenic patients (Schmitt et al., 2005).
Heat shock 70-kDa proteins (HSP70s) are molecular chaperones and also microglial activators, which regulate biological processes and are associated with the pathophysiology of schizophrenia. Antibodies against HSP70 have been found in the serum of schizophrenic patients, which is suggestive of inflammation (Kim et al., 2001 and Kim et al., 2008). Extracellular HSP70 mediates the innate immune responses of brain through toll-like receptors (TLRs). TLRs activate the nuclear transcription factor kappa B (NF-κB), which plays a key role in the expression of genes responsible for the development of cell and inflammation. These transcription factors also are capable of activating the promoter region of many pro-inflammatory genes, including genes expressed by the M1 microglial phenotype (Tato and Hunter, 2002 and Saijo and Glass, 2011).”
“…inhibition of pro-inflammatory cytokines or enhancement of anti-inflammatory mediators in schizophrenic patients may be a beneficial strategy to prevent the devastating consequences of this illness with respect to neuronal damage and function. We propose that inhibition of the activity of DAMPs and/or administration of specific anti-inflammatory agents may lead to amelioration of symptoms of this debilitating illness.”
Recent findings strongly support the idea to use anti-inflammatory drugs such as minocycline to target microglia activation as an adjunctive therapy in schizophrenic patients.
In both schizophrenia and depression immunological imbalance results in increased prostaglandin E2 (PE2) production and probably also in increased cyclooxygenase-2 (COX-2) expression – COX-2 inhibition is a potential therapeutic strategy .
“Classical inflammatory cytokines, such as IL-1β, TNF-α and IL-6, by activating their cognate receptors in target cells, induce intracellular pathways which differ depending on the cell type, and often result in divergent pathophysiologic outcomes. In the nervous system, cytokines have physiological functions that include neurite outgrowth, neurogenesis, neuronal survival, synaptic pruning during brain development, and they regulate the strength of synaptic transmission and synaptic plasticity”
The versatility in VGCs enables them to regulate various cellular pathophysiologic processes, ranging from neuronal excitability and synaptic transmission to neuronal death or survival. Cytokines are among the molecules that influence VGCs properties, and as such they are now regarded as novel neuromodulators. The modulation of VGCs by cytokines is reviewed extensively in the article.
Modulation of receptor-coupled ion channels in CNS by cytokines:
In hippocampal neurons, IL-1R1 co-localizes with the N-methyl-d-aspartate receptor
NMDAR stimulation increases the IL-1R1 interaction with the NR2B subunit
increases the GABAergic tone, thus altering the synaptic strength at GABAergic synapses.
modulates exocytosis of several neurotransmitters such as norepinephrine, glutamate, GABA and adenosine
there is evidence of presynaptic effects of IL-1β on glutamatergic terminals resulting in modulation of glutamate release.
precludes the cannabinoid CB1 receptors ability to inhibit glutamate release in corticostriatal brain slices, an effect that presumably increases neuronal network excitability.
induces defects in GABAergic neurotransmission in forebrain
has predominant excitatory effects mediated by enhancement of NMDA-induced neuronal Ca2+ influx, increased glutamate release, and inhibitory effects on GABAergic neurotransmission.
has specific interactions with AMPAR mediated by TNF-R1 (reversed by activation of cannabinoid CB1 receptors)
promotes the endocytosis of GABA-A receptors expressing the β2/3 subunits, thereby reducing inhibitory synaptic transmission
modulates glutamate and GABA receptor subunit compositions at neuronal membranes
can modify extracellular glutamate levels indirectly, by inducing glutamate release from microglia and astrocytes
Recently it was found that infliximab (a TNF-α inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress model of depression, suggesting that inflammation might play an important role in stress related illnesses . TNF-α is important to the sensitivity of the behavioral response to administration of antidepressants . It has been suggested that pro-inflammatory cytokines enhance serotonin transporter activity, and possibly also dopamine transporter activity in the brain .
reduces glutamate excitotoxicity
reduces mGLUR2/3 metabotropic receptor expression
reduces AMPAR-GLUR2 subunit and L-type Ca2+ channel proteins
alters the functional properties of hippocampal synaptic network activity, especially under conditions of strong synaptic drive
reduces NMDA-activated neuronal firing in rat cerebellar slices, an effect associated with decreased NR1 subunit phosphorylation
Elevated IL-6 levels may play the role in cognitive impairment and serve as potential inflammatory biomarker of deterioration in schizophrenia . IL-6 directly controls SERT levels and consequently serotonin reuptake  and can regulate 5-HT2A receptor function .
Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established – but puzzling – findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia.
Bolstering immune function
One treatment strategy suggested by the hypothesis would be to employ practices that bolster immune function, by helping schizophrenia patients to follow procedures that have been shown to reduce inflammatory responses and improve defense against infection. These include, for example, insuring a balanced diet and ample levels of sunlight exposure, to insure adequate levels of vitamin D. A complementary approach would insure that patients practice regular moderate exercise and stress management—a regimen that some controlled experiments have found to reduce inflammation and improve resistance to infectious diseases.
Diagnosing and treating unrecognized infections and immune disorders
Because the hypothesis suggests that schizophrenia patients’ symptoms may sometimes be promoted by unrecognized and/or untreated infections, another strategy could involve more careful testing for untreated infections, and trials with targeted anti-viral or antibiotic regimes. Similarly, treating previously unrecognized immune disorders, or investigating medications to reduce high levels of pro-inflammatory cytokines, could be an informative test. As part of their disability, schizophrenia patients are less likely to seek out medical care and/or follow treatment recommendations. Thus, it may become important to regularly screen for infections as part of standard psychiatric care. Of note, adherence to anti-viral, antibiotic, or anti-inflammatory medication regimes may be greater than adherence to antipsychotics, as they tend to be better-tolerated, and carry less illness-related fear and stigma.
New prevention strategies
Reducing exposure to new infections
Primary prevention by optimizing prenatal care and nutrition