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Microdeletions at the 22q11.2 locus are associated with increased risk for schizophrenia. Recent work has demonstrated that antipsychotic naïve 22q11.2 carriers display elevated levels of dopamine synthesis capacity (DSC) as assessed by

BackgroundAutism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post-mortem brain studies using adult brains have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from autistic individuals with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism.MethodsIPSCs were generated from 9 unrelated autistic individuals without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing, control, individuals. IPSCs were differentiated towards either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterise iPSCs at different stage of differentiation.ResultsA subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to post-mortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated towards a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors, and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs.ConclusionsTaken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

Additional file 1. Additional Methods, Figures and Tables.

Autism spectrum conditions (ASCs) are neurodevelopmental in origin and entail social-communication disability alongside unusually narrow interests and difficulties adjusting to unexpected change. The cause of ASCs is complex due to the interplay of an array of genetic and environmental factors. Although ASCs are known to be highly heritable, genetic sequencing and association studies have identified only a fraction of the total number of genes thought to be associated with the condition. Nevertheless, neither genetic components nor environmental factors have been able to elucidate the pathophysiology of nonsyndromic ASCs. Recently there has been a paradigm shift in autism research toward investigating how environment mediates gene expression subsequently affecting biological pathways crucial for brain development. In this chapter, we discuss the key epigenetic mechanisms, such as DNA methylation and histone modifications, as potential contributors to the etiopathogenesis of ASCs. We also highlight some of the risk factors affecting autism epigenetics, the limitations of current research, and the implications for future work.

Japanese encephalitis virus (JEV) is a common cause of encephalitis in humans who are dead-end hosts producing negligible viremia. The virus reaches the brain and causes massive inflammation. Our study seeks to understand the virus-host interaction using the murine monocyte/macrophage cell line RAW264.7, an antigen presenting cell involved in eliciting an innate immune response. We have discovered several interesting phenomena occurring in JEV-infected RAW264.7 cells which diverge from established observations. JEV remains inside RAW264.7 and appears to have little negative effect on cell viability. Expression studies of major histocompatibility complexes (MHC) and co-stimulatory molecules show inhibition of antigen presentation. There is enhanced immune suppression creating an anti-viral milieu. Expression of pro-inflammatory cytokines and chemokines is suppressed along with increased expression of anti-inflammatory molecules. Histone deacetylases (HDACs) have known inflammatory properties. In our study, through modulation of HDACs JEV seems to induce a crucial anti-inflammatory and anti-viral role in host macrophages.

Japanese encephalitis (JE) is a mosquitoborne viral disease that is the primary cause of acute encephalitis syndrome in India. This virus mainly infects the central nervous system and causes massive inflammation which, if left unchecked, may prove fatal. Survivors often suffer from mild to severe neuropsychiatric sequelae. JE is a major cause of death in many parts of India and there is a possibility of it spreading into the National Capital Region from highly endemic neighbouring states. Fourteen cases of JE were reported in Delhi in 2011 compared with none in the previous 4 years from 2007 to 2010. Unless immediate preventive measures are taken this trend could continue and the disease could spread with increasing prevalence.

Viruses have evolved with their hosts, which include all living species. This has been partly responsible for the development of highly advanced immune systems in the hosts. However, viruses too have evolved ways to regulate and evade the host’s immune defence. In addition to mutational mechanisms that viruses employ to mimic the host genome and undergo latency to evade the host’s recognition of the pathogen, they have also developed epigenetic mechanisms by which they can render the host’s immune responses inactive to their antigens. The epigenetic regulation of gene expression is intrinsically active inside the host and is involved in regulating gene expression and cellular differentiation. Viral immune evasion strategies are an area of major concern in modern biomedical research. Immune evasion strategies may involve interference with the host antigen presentation machinery or host immune gene expression capabilities, and viruses, in these manners, introduce and propagate infection. The aim of this review is to elucidate the various epigenetic changes that viruses are capable of bringing about in their host in order to enhance their own survivability and pathogenesis.

Background Japanese encephalitis virus (JEV) induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline. Methodology/Principal Findings Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE) and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used. Conclusion/Significance This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors.