Schizophrenia is a complex neuropsychiatric disorder that is characterized by delusions, hallucinations, disorganized behavior and progressive cognitive deficits with postulated neurodevelopmental origin., The neurodevelopmental pathogenetic model implicates schizophrenia as a behavioural outcome of impaired neurodevelopmental processes that begins long before the onset of clinical symptoms and is caused by a combination of genetic, immune and environmental factors. Among these factors, multiple susceptibility genes regulated by hypoxia are shown to enhance the risk of schizophrenia by interacting with serious obstetric complications. In addition, it is noteworthy that prenatal infections with resultant persistent pro-inflammatory state leading to aberrant neurodevelopment as well as obstetric complications are also shown to confer increased risk for schizophrenia. Epidemiological observations strongly support the association between elevated risk for schizophrenia in the offspring and prenatal exposure to influenza, toxoplasma, rubella, genital-reproductive infections and various other infections. It is noteworthy that multiple immune mediators such as cytokines, major histocompatibility complex (MHC) molecules etc. critically modulate the brain development during the prenatal stages., However, prenatal infection by various viral, bacterial and protozoan pathogens have been found to alter the expression of various immune molecules and contribute to early development etiology of schizophrenia. Interestingly, over the past many decades, influential theoretical propositions (Geschwind-Behan-Galaburda hypothesis,, being principal among them) and evidence base (albeit not unequivocally) have compellingly linked prenatal sex hormonal status to altered immune functions. Collectively, such sex hormones and immune system interactions during prenatal period have been shown to modulate cerebral asymmetry (comprehensively reviewed in the article of Stoyanov et al.). Accumulating evidence increasingly implicates the significance of immune-inflammatory and neuroendocrinological processes as well as abnormalities in cerebral asymmetry in the pathogenesis of at least in a subset of patients with schizophrenia. In this review, we summarize the select perspectives emphasizing the role of immune-inflammatory aberrations and their interactions with cerebral asymmetry abnormalities in contemporary understanding of schizophrenia pathogenesis.
This has prompted renewed interest in cytokines as markers of immune imbalance in schizophrenia and cytokine-centered hypotheses of schizophrenia pathogenesis have been recently proposed .
Severe fatigue is a common complaint among patients
Deficits in hippocampus with associated disturbances in its network brain regions are among the most established findings in schizophrenia.,, Recent studies suggest compelling support for the effect of IL-6 and IGF-1 on hippocampal structure and function. Peripheral levels of IL-6 have been shown to have a significant inverse correlation with gray matter volume of hippocampus. Both IGF-1 and IL-6 influence the functioning of hippocampus - an important brain region involved the pathogenesis of schizophrenia, IGF-1 improves hippocampal functioning whereas IL-6 damages it. The human IL-6 gene is located on chromosome 7p15-7p21 and IL-6 expression is primarily regulated by alterations in gene transcription. A functional G→C single-nucleotide polymorphism at position -174 of the promoter has been described. Genetic and expression studies suggested that the GG allele was associated with greater induction of IL-6 compared with the GC or CC alleles. Hence, it is possible that MIA might result in persistent over-activation of glial cells which could be more pronounced in individuals who are predisposed towards greater induction of IL-6 and various other inflammatory cytokines; these pathogenetic mechanisms might lead to hippocampal network damage culminating in symptoms of schizophrenia.