Schizophrenia is a psychiatric disorder with a prevalence of one percent in the general population (1). Individuals affected by the illness endure periods of psychosis, accompanied by a large individual and social burden. The disorder can be characterised by a variety of symptoms, including hallucinations, delusions, thought disorder, social withdrawal, apathy, and cognitive deficits (2). The onset of these symptoms generally occurs between late adolescence and early 30s.
Historically, the pathophysiology of schizophrenia was hypothesised to involve deficiencies in neurodevelopment (3). Neurodevelopment in general has a growth stage in early development and a pruning stage. The former is predominant in early development whereas the latter occurs throughout lifetime, but especially during puberty. The neurodevelopmental hypothesis has been substantiated by reports of abnormalities in processes typically associated with development, these being neuronal proliferation, migration, myelination, and synaptic plasticity (4). The multi-hit model postulates that certain gene-environmental interactions affect these processes at pivotal stages during prenatal, early, and adolescent neurodevelopment, thereby predisposing a person to develop schizophrenia (5, 6). Correspondingly, genetic epidemiology has revealed various environmental stressors, such as childhood trauma and maternal infection, and genetic risks associated with the disorder (4).
With respect to the underlying pathogenic mechanisms, accumulating evidence indicates that neuroinflammation, specifically chronic inflammation of the central nervous system (CNS), may play a central role in the aetiology of schizophrenia (7, 8). The aforementioned gene-environmental interactions, like childhood trauma, potentially cause hyperactivation of the peripheral immune system and subsequent permeability of the blood brain barrier (9). Several studies reported indeed an increase in pro-inflammatory cytokines in individuals with schizophrenia (5). Consequently, pass over of peripheral immune cells and/or molecules into the CNS might occur, thereby inducing inflammation. Prolonged CNS inflammation damages the brain parenchyma and sensitises the residing microglia to future inflammatory events (10). Moreover, inflammatory factors may directly interfere with neural signalling (8, 11).
Genome-wide association studies support the notion that in the pathophysiology of schizophrenia there are alterations in neuronal and immune signalling (7, 8, 12). In fact, the Psychiatric Genomics Consortium wave 3 genome-wide association study indicated that both inflammatory and glutamatergic signalling genes are associated with schizophrenia (13). Glutamate is the most prominent excitatory neurotransmitter and facilitates synaptic plasticity by acting on receptors such as the ionotropic N-methyl-D-aspartate (NMDA) receptor (11, 14). Additionally, NMDAR containing parvalbumin inhibitory interneurons in the prefrontal cortex modulate dopaminergic activity in the mesocortical and mesolimbic systems. Dysregulation of dopamine levels in these areas has been associated with negative and positive symptoms, respectively (7, 11, 15). Astrocytes are responsible for glutamate uptake from the synaptic cleft as well as glutamate conversion into glutamine, which can be transported to presynaptic glutamatergic neurons and be converted back into glutamate (12). Pro-inflammatory cytokines, however, can alter astrocytic functioning. In combination with abnormal expression of glutamatergic genes, this might dysregulate the glutamate system. Consequently, excitotoxicity, NMDA-receptor hypofunction, and reduced synaptic plasticity may be the physiological consequence (11).
Alternatively, several immune-related genes and loci can help to maintain neurological processes involved in schizophrenia, examples include TLR4, IL-6, TGFβ, and CRP (7, 11). The most well-known locus is the major histocompatibility complex located on chromosome 6 region 6p22.1-6p21.3 (16, 17). In particular, genes encoding for proteins of the complement system have been associated in the pathogenesis (17, 18). The complement system comprises a comprehensive set of proteins essential for the host defence against invading microorganisms and clearance of injured cells. Within the CNS, however, this system is also involved in synaptic pruning, neuronal migration, and proliferation (16, 18, 19).
The knowledge about all these molecular processes can be used for data analysis using molecular, machine readable pathways. These pathways provide an interactive representation of biological pathways, including interactions between genes, metabolites, and proteins as well as proper annotation and literature references (20). WikiPathways allows creation and publication of community created, but expert curated pathways in its repository (21). Pathway analysis positions the omics data in the context of these pathways and associated biological functions. Additionally, it facilitates the assessment of how pathway components are expressed in different samples.
Regarding schizophrenia, pathway curation and analysis allows for a comprehensive and dynamic visualisation of missing pathways representing the emerging neurodevelopmental roles of the complement system, astrocytes, and neuroinflammation. In combination with Gene Ontology (GO) and network analysis, it indicates the contributions of specific risk genes, biological processes, and transcription factors to development of schizophrenia. Furthermore, this could help reveal potential targets for new therapeutic strategies. Hence, the aim of the current study was to create and publish interactive biological pathways involved in schizophrenia (with focus on immunology and glutamate) and use them for the identification of novel pharmacological targets based on transcriptomics analysis consisting of pathway, GO, and network analysis.