Monojit Debnath

Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia

In recent decades, a significant role for altered immunoinflammatory, oxidative and nitrosative stress (IO&NS) pathways in schizophrenia has been recognized (Smith and Maes, 1995; Wood et al., 2009). Importantly, such processes have provided crucial clues to the etiology, course and management of this devastating disorder. This is the focus of this special edition. Epidemiological findings supporting a role for prenatal viral, bacterial and protozoan infections in the etiology of schizophrenia have provided a seminal contribution to the neurodevelopmental hypothesis of schizophrenia (Brown and Derkits, 2010). The early developmental etiology of schizophrenia to a lesser extent has been focused on decreased vitamin D in early development, including via vitamin D modulation of the immune response to infection (McGrath et al., 2003). Interactions between these factors is suggested by the fact that vitaminDhas a documented role in immunemodulation, especially during placental development and in early childhood (Battersby et al., 2012; Liu et al., 2011). The maximal risk period for maternal infection association with offspring schizophrenia is shown to be early pregnancy (Brown et al., 2004; Khandaker et al., 2012). Interestingly many schizophrenia susceptibility genes are regulated by hypoxia, suggesting close interactions among IO&NS genes and obstetric complications leading to enhanced risk of schizophrenia (Nicodemus et al., 2008; Schmidt-Kastner et al., 2006). Other conditions of pregnancy, including hypoxia associated preeclampsia (Kendell et al., 1996), also increase the risk of the offspring being classed as having schizophrenia, emphasizing the profound impact of prenatal events. The evidence for the role of prenatal infection, both epidemiological and experimental, is excellently reviewed byUrsMeyer (2013–this issue) who has published extensively in this area. Many of the developmental effects of infection are driven not only by O&NS and proinflammatory cytokine increases in the placenta and fetus, but also by associated hypoferremia and zinc deficiency (Ganz and Nemeth, 2009; Prasad, 2009). Such changes render the offspring prone to subsequent second hits over the course of post-natal development, contributing to both the emergence and progression of disease manifestations. This is an important area of experimental research given that the elimination of the effects of maternal infection is estimated to decrease the incidence of schizophrenia by as much as 46% (Brown and Derkits, 2010).

Mitochondrial dysfunction in schizophrenia: Pathways, mechanisms and implications

Mitochondria play a critical role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signalling, and apoptotic cell death. Mitochondria are also essential to many aspects of neurodevelopment and neuronal functions. However, mitochondrial impairment may affect bioenergetics in the developing brain and alter critical neuronal processes leading to neurodevelopmental abnormalities. Schizophrenia is a chronic and severe neuropsychiatric disorder of neurodevelopmental origin. Immuno-inflammatory pathway is one of the widely appreciated mechanisms that has consistently been implicated in the neurodevelopmental origin of schizophrenia. However, the source of inflammation and the underlying neurobiological mechanisms leading to schizophrenia are yet to be fully ascertained. Recent understanding reveals that perturbation of mitochondrial network dynamics might lead to various nervous system disorders with inflammatory pathologies. Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia. Herein, we summarise the current understanding of molecular links between mitochondrial dysfunctions and pathogenesis of schizophrenia based on evidence from genomics, proteomics and imaging studies, which together support a role for mitochondrial impairment in the pathogenetic pathways of schizophrenia.

A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis.

Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype-the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders.

Th17 Pathway–Mediated Immunopathogenesis of Schizophrenia: Mechanisms and Implications

Schizophrenia is a highly complex and severe neuropsychiatric disorder with an unknown etiopathology. Evidence for a dysregulated immune system in both the risk for and progression of schizophrenia has recently been overwhelming. Importantly, chronic low-grade inflammation both in the periphery and central nervous system has been shown to contribute predominantly to the pathogenesis of schizophrenia in a subset of individuals. Inflammation in the central nervous system is mediated by a range of proinflammatory cytokines, resident immune cells such as microglia, and brain infiltrating peripheral immunocompetent cells, such as T lymphocytes. Recently, Th17 cells, a subset of T helper cells have emerged as crucial players in mucosal defense against infections. It is linked to atopic, inflammatory, and autoimmune disorders. The risk factors/mechanisms leading to low-grade inflammation in schizophrenia are diverse and include infectious agents, stress, trauma, environmental toxins, genetic vulnerability, physical inactivity, obesity, poor diet, and sleep disruption. Herein, we propose that fetal programming of cellular immune components driven by intrauterine adversity can lead to the generation of long-lasting effector/memory Th17 cells. Th17 cells can disrupt the blood-brain barrier, infiltrate the central nervous system, and, along with other cytokines and microglia, lead to neuroprogression through neuroinflammation in schizophrenia.

Variation in the major histocompatibility complex [MHC] gene family in schizophrenia: associations and functional implications.

Schizophrenia is a chronic debilitating neuropsychiatric disorder with a complex genetic contribution. Although multiple genetic, immunological and environmental factors are known to contribute to schizophrenia susceptibility, the underlying neurobiological mechanism(s) is yet to be established. The immune system dysfunction theory of schizophrenia is experiencing a period of renewal due to a growth in evidence implicating components of the immune system in brain function and human behavior. Current evidence indicates that certain immune molecules such as Major Histocompatibility Complex (MHC) and cytokines, the key regulators of immunity and inflammation are directly involved in the neurobiological processes related to neurodevelopment, neuronal plasticity, learning, memory and behavior. However, the strongest support in favor of the immune hypothesis has recently emerged from on-going genome wide association studies advocating MHC region variants as major determinants of ones risk for developing schizophrenia. Further identification of the interacting partners and receptors of MHC molecules in the brain and their role in down-stream signaling pathways of neurotransmission have implicated these molecules as potential schizophrenia risk factors. More recently, combined brain imaging and genetic studies have revealed a relationship between genetic variations within the MHC region and neuromorphometric changes during schizophrenia. Furthermore, MHC molecules play a significant role in the immune-infective and neurodevelopmental pathogenetic pathways, currently hypothesized to contribute to the pathophysiology of schizophrenia. Herein, we review the immunological, genetic and expression studies assessing the role of the MHC in conferring risk for developing schizophrenia, we summarize and discuss the possible mechanisms involved, making note of the challenges to, and future directions of, immunogenetic research in schizophrenia.

Fetal programming of schizophrenia: Select mechanisms

Abstract Mounting evidence indicates that schizophrenia is associated with adverse intrauterine experiences. An adverse or suboptimal fetal environment can cause irreversible changes in brain that can subsequently exert long-lasting effects through resetting a diverse array of biological systems including endocrine, immune and nervous. It is evident from animal and imaging studies that subtle variations in the intrauterine environment can cause recognizable differences in brain structure and cognitive functions in the offspring. A wide variety of environmental factors may play a role in precipitating the emergent developmental dysregulation and the consequent evolution of psychiatric traits in early adulthood by inducing inflammatory, oxidative and nitrosative stress (IO&NS) pathways, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. However, the precise mechanisms behind such relationships and the specificity of the risk factors for schizophrenia remain exploratory. Considering the paucity of knowledge on fetal programming of schizophrenia, it is timely to consolidate the recent advances in the field and put forward an integrated overview of the mechanisms associated with fetal origin of schizophrenia.

Y-chromosome haplogroup diversity in the sub-Himalayan Terai and Duars populations of East India

The sub-Himalayan Terai and Duars, the important outermost zones comprising the plains of East India, are known as the reservoirs of ethnic diversity. Analysis of the paternal genetic diversity of the populations inhabiting these regions and their genetic relationships with adjacent Himalayan and other Asian populations has not been addressed empirically. In the present investigation, we undertook a Y-chromosome phylogeographic study on 10 populations (n=375) representing four different linguistic groups from the sub-Himalayan Terai and Duars regions of East India. The high-resolution analysis of Y-chromosome haplogroup variations based on 76 binary markers revealed that the sub-Himalayan paternal gene pool is extremely heterogeneous. Three major haplogroups, namely H, O and R, are shared across the four linguistic groups. The Indo-European-speaking castes exhibit more haplogroup diversity than the tribal groups. The findings of the present investigation suggest that the sub-Himalayan gene pools have received predominant Southeast Asian contribution. In addition, the presence of Northeast and South Asian signatures illustrate multiple events of population migrations as well as extensive genetic admixture amongst the linguistic groups.

Lack of association of IL-6 (-174 G>C) and TNF-α (-238 G>A) variants with paranoid schizophrenia in Indian Bengalee population.

Schizophrenia is a chronic debilitating neuropsychiatric disorder with complex etiopathology. Growing evidence suggests a significant role of chronic low grade inflammation in the pathophysiology of schizophrenia. Multiple immunological, genetic polymorphism and gene expression studies have established crucial roles of certain pro-inflammatory cytokines in the immune-mediated risk of schizophrenia. Although genetic studies suggest some variants within the pro-inflammatory IL-1β, IL-6, and TNF-α genes conferring risk to schizophrenia, the results however have been contradictory in various populations. In the present investigation, promoter SNPs of IL-6 (-174 G>C) and TNF-α (-238 G>A) genes have been studied to evaluate whether these variants contribute to schizophrenia susceptibility in Indian Bengalee population. Genotyping of the above SNPs was done in 100 well characterized and confirmed cases of paranoid schizophrenia and equal number of healthy donors belonging to the same ethnic group by using ABI 3730 Genetic Analyzer. No significant differences in genotype as well as allele frequencies were observed for IL-6 and TNF-α variants between the patient and control groups.

Recent advances in psychoneuroimmunology: Inflammation in psychiatric disorders

Psychiatric disorders are common and complex and their precise biological underpinnings remain elusive. Multiple epidemiological, molecular, genetic and gene expression studies suggest that immune system dysfunction may contribute to the risk for developing psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder. However, the precise mechanisms by which inflammation-related events confer such risk are unclear. In this review, we examine the peripheral and central evidence for inflammation in psychiatric disorders and the potential molecular mechanisms implicated including inhibition of neurogenesis, apoptosis, the HPA-axis, the role of brain-derived neurotrophic factor and the interplay between the glutamatergic, dopaminergic and serotonergic neurotransmitter systems.

Transcranial direct current stimulation and neuroplasticity genes: implications for psychiatric disorders

Background and Aim Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders. Method A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms. Result Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials. Conclusion Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry.