Epigenetic modifications are increasingly recognized to play a role in the etiology and pathophysiology of schizophrenia and other psychiatric disorders with developmental origins. Here, we summarize ...clinical and preclinical findings of epigenetic alterations in schizophrenia and relevant disease models and discuss their putative origin. Recent findings suggest that certain schizophrenia risk loci can influence stochastic variation in gene expression through epigenetic processes, highlighting the intricate interaction between genetic and epigenetic control of neurodevelopmental trajectories. In addition, a substantial portion of epigenetic alterations in schizophrenia and related disorders may be acquired through environmental factors and may be manifested as molecular “scars.” Some of these scars can influence brain functions throughout the entire lifespan and may even be transmitted across generations via epigenetic germline inheritance. Epigenetic modifications, whether caused by genetic or environmental factors, are plausible molecular sources of phenotypic heterogeneity and offer a target for therapeutic interventions. The further elucidation of epigenetic modifications thus may increase our knowledge regarding schizophrenia’s heterogeneous etiology and pathophysiology and, in the long term, may advance personalized treatments through the use of biomarker-guided epigenetic interventions.
Epidemiologic studies, including prospective birth cohort investigations, have implicated maternal immune activation in the etiology of neuropsychiatric disorders. Maternal infectious pathogens and ...inflammation are plausible risk factors for these outcomes and have been associated with schizophrenia, autism spectrum disorder, and bipolar disorder. Concurrent with epidemiologic research are animal models of prenatal immune activation, which have documented behavioral, neurochemical, neuroanatomic, and neurophysiologic disruptions that mirror phenotypes observed in these neuropsychiatric disorders. Epidemiologic studies of maternal immune activation offer the advantage of directly evaluating human populations but are limited in their ability to uncover pathogenic mechanisms. Animal models, on the other hand, are limited in their generalizability to psychiatric disorders but have made significant strides toward discovering causal relationships and biological pathways between maternal immune activation and neuropsychiatric phenotypes. Incorporating these risk factors in reverse translational animal models of maternal immune activation has yielded a wealth of data supporting the predictive potential of epidemiologic studies. To further enhance the translatability between epidemiology and basic science, the authors propose a complementary approach that includes deconstructing neuropsychiatric outcomes of maternal immune activation into key pathophysiologically defined phenotypes that are identifiable in humans and animals and that evaluate the interspecies concordance regarding interactions between maternal immune activation and genetic and epigenetic factors, including processes involving intergenerational disease transmission. AJP AT 175: Remembering Our Past As We Envision Our Future October 1857: The Pathology of Insanity J.C. Bucknill: "In the brain the state of inflammation itself either very quickly ceases or very soon causes death; but when it does cease it leaves behind it consequences which are frequently the causes of insanity, and the conditions of cerebral atrophy." (Am J Psychiatry 1857; 14:172-193 ).
Nanomaterial engineering provides an important technological advance that offers substantial benefits for applications not only in the production and processing, but also in the packaging and storage ...of food. An expanding commercialization of nanomaterials as part of the modern diet will substantially increase their oral intake worldwide. While the risk of particle inhalation received much attention, gaps of knowledge exist regarding possible adverse health effects due to gastrointestinal exposure. This problem is highlighted by pigment-grade titanium dioxide (TiO
), which confers a white color and increased opacity with an optimal particle diameter of 200-300 nm. However, size distribution analyses showed that batches of food-grade TiO
always comprise a nano-sized fraction as inevitable byproduct of the manufacturing processes. Submicron-sized TiO
particles, in Europe listed as E 171, are widely used as a food additive although the relevant risk assessment has never been satisfactorily completed. For example, it is not possible to derive a safe daily intake of TiO
from the available long-term feeding studies in rodents. Also, the use of TiO
particles in the food sector leads to highest exposures in children, but only few studies address the vulnerability of this particular age group. Extrapolation of animal studies to humans is also problematic due to knowledge gaps as to local gastrointestinal effects of TiO
particles, primarily on the mucosa and the gut-associated lymphoid system. Tissue distributions after oral administration of TiO
differ from other exposure routes, thus limiting the relevance of data obtained from inhalation or parenteral injections. Such difficulties and uncertainties emerging in the retrospective assessment of TiO
particles exemplify the need for a fit-to-purpose data requirement for the future evaluation of novel nano-sized or submicron-sized particles added deliberately to food.
Beyond their contribution to the metabolism of xenobiotics, cytochrome P450 (CYP) epoxygenases are actively involved in the metabolism of endogenous substances, like arachidonic acid (AA). The main ...human CYP epoxygenases, i.e. CYP2C8, CYP2C9, CYP2C19 and CYP2J2, convert AA to four regioisomer epoxyeicosatrienoic acids (EETs). EETs possess a wide range of established protective effects on the human cardiovascular system of which anti-inflammatory actions have gained great recent interest. The expression of CYP epoxygenases is regulated through an extremely complex network of nuclear receptors, microRNAs and genetic/epigenetic factors. Accordingly, a large number of biological variables as well as xenobiotics and environmental factors can influence the expression of CYP epoxygenases, resulting in a significant intra- and inter-individual variability in the expression and activity of these enzymes and subsequently in EET biosynthesis. Moreover, human CYP epoxygenases are mainly expressed in the liver; however, these enzymes are also expressed, at various extents, in most extrahepatic tissues, resulting in a marked inter-tissue variability in the expression of CYP epoxygenases. The inter-tissue, inter- and intra-individual variability in the expression of epoxygenases may lead to differences in the relative abundance of EETs among tissues, among individuals of a population and/or different ethnicities and in a given individual under various conditions. The variation in the abundance of EETs may explain, at least in part, the inter-tissue and inter-individual differences observed in the prevalence of inflammation-related disorders including cardiovascular disease, and why in a given individual, various conditions can contribute to the development of diseases with an important inflammatory component.
Maternal immune activation (MIA), be it triggered by infectious or noninfectious stimuli, is implicated in various psychiatric and neurological disorders with developmental etiologies. Its ...consequences on the offspring’s mental health are heterogeneous and influenced by a number of factors shaping the specificity and/or severity of pathological outcomes. There is also a substantial degree of resilience to MIA, which determines the extent to which offspring are protected from developing neurodevelopmental sequelae. This review provides a synopsis of the plausible sources that account for the heterogeneous outcomes of MIA and discusses key factors that are critical for establishing neurodevelopmental resilience and susceptibility to this early-life adversity.
Maternal immune activation (MIA) during pregnancy is increasingly recognized as an etiological risk factor for various psychiatric and neurological disorders.Whereas a substantial portion of offspring is resilient to the consequences of MIA, susceptible offspring may develop overt physical, neurological, and/or mental disorders.Various factors can promote susceptibility to the effects of MIA, including maternal hypoferremia and anemia, gestational diabetes mellitus, maternal stress during pregnancy, dysbiosis of the maternal gut microbiota, peripubertal exposure to psychological trauma, and chronic cannabis use during periadolescence.Factors that can promote resilience to the effects of MIA include high maternal status for vitamin D, iron, zinc, or choline, efficient anti-inflammatory and antioxidant response systems, and the availability of omega-3 fatty acids.
It is increasingly appreciated that altered neuroimmune mechanisms might play a role in the development of schizophrenia and related psychotic illnesses. On the basis of human epidemiological ...findings, a number of translational rodent models have been established to explore the consequences of prenatal immune activation on brain and behavioral development. The currently existing models are based on maternal gestational exposure to human influenza virus, the viral mimic polyriboinosinic-polyribocytidilic acid Poly(I:C), the bacterial endotoxin lipopolysaccharide, the locally acting inflammatory agent turpentine, or selected inflammatory cytokines. These models are pivotal for establishing causal relationships and for identifying cellular and molecular mechanisms that affect normal brain development in the event of early-life immune exposures. An important aspect of developmental immune activation models is that they allow a multi-faceted, longitudinal monitoring of the disease process as it unfolds during the course of neurodevelopment from prenatal to adult stages of life. An important recent refinement of these models is the incorporation of multiple etiologically relevant risk factors by combining prenatal immune challenges with specific genetic manipulations or additional environmental adversities. Converging findings from such recent experimental attempts suggest that prenatal infection can act as a “neurodevelopmental disease primer” that is likely relevant for a number of chronic mental illnesses. Hence, the adverse effects induced by prenatal infection might reflect an early entry into the neuropsychiatric route, but the specificity of subsequent disease or symptoms is likely to be strongly influenced by the genetic and environmental context in which the prenatal infectious process occurs.
Physicians have long been aware of the subtle differences in the responses of patients to medication. The recognition that a part of this variation is inherited, and therefore predictable, created ...the field of pharmacogenetics fifty years ago. Knowing the gene variants that cause differences among patients has the potential to allow 'personalized' drug therapy and to avoid therapeutic failure and serious side effects.
Highlights • Maternal poly(I:C) challenge induces presynaptic hippocampal deficits in adult offspring. • Prenatal immune activation leads to postsynaptic hippocampal deficits in pubescence. • ...Hippocampal IL-1β is increased in adulthood without signs of systemic inflammation. • Synaptic deficits occur in absence of microglial anomalies.
Background Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, ...we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution. Methods Prenatal immune activation was induced by maternal treatment with the viral mimetic poly(I:C) in middle or late gestation. Following behavioral and cognitive characterization of the adult offspring ( N = 12 per group), unbiased capture array bisulfite sequencing was combined with subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and quantitative real-time PCR analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. GO term enrichment analysis was used to explore shared functional pathways of genes with differential DNA methylation. Results Adult offspring of immune-challenged mothers displayed hyper- and hypomethylated CpGs at numerous loci and at distinct genomic regions, including genes relevant for GABAergic differentiation and signaling (e.g., DLX1, LHX5, LHX8), Wnt signaling (WNT3, WNT8A, WNT7B), and neural development (e.g., EFNB3, MID1, NLGN1, NRX2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring’s age and were markedly influenced by the precise timing of prenatal immune activation. Conclusions Prenatal viral-like immune activation is capable of inducing stable DNA methylation changes in the medial prefrontal cortex. These long-term epigenetic modifications are a plausible mechanism underlying the disruption of prefrontal gene transcription and behavioral functions in subjects with prenatal infectious histories.
Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that ...neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease.
The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging.
We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Aβ peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD.
Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Aβ plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.
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