Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder : focus on biological pathways and epigenetic mechanisms

When considering neurodevelopmental disorders (NDDs), Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) are considered to be among the most severe in term of prevalence, morbidity and impact on the society. Similar features and overlapping symptoms have been observed at multiple levels, suggesting common pathophysiological bases. Indeed, recent genome-wide association studies (GWAS) and epidemiological data report shared vulnerability genes and environmental triggers across the two disorders. In this review, we will discuss the possible biological mechanisms, including glutamatergic and GABAergic neurotransmissions, inflammatory signals and oxidative stress related systems, which are targeted by adverse environmental exposures and that have been associated with the development of SZ and ASD. We will also discuss the emerging role of the gut microbiome as possible interplay between environment, immune system and brain development. Finally, we will describe the involvement of epigenetic mechanisms in the maintenance of long-lasting effects of adverse environments early in life. This will allow us to better understand the pathophysiology of these NDDs, and also to identify novel targets for future treatment strategies

LATE PRENATAL INFECTION AND NEURODEVELOPMENTAL DISORDERS: CHARACTERIZATION OF AN IMMUNE-MEDIATED MOUSE MODEL

Compelling evidence suggests that the aetiology of multifactorial and multisymptomatic psychiatric diseases include exposures to adverse events during prenatal and early postnatal life, which may disrupt the correct maturation of neural system and lead to long-lasting changes in brain function. Prenatal insults, and in particular prenatal infection, could thus act as a \u201cprimer\u201d for the neuropsychiatric route, even if the specificity of the illness that develops is strongly influenced by the genetic and environmental context in which the process occurs (Meyer, 2013b). A similar concept of \u201cearly-life programming of adult disease\u201d has been put forward by the seminal work of David Barker conducted in the context of cardiovascular disease (Dover, 2009), suggesting that specific environmental factors acting during sensitive prenatal or early postnatal developmental periods can induce persistent changes in physiological, emotional and behavioural functions throughout life (Bale et al, 2010). Against this background, the aim of my PhD thesis was to investigate and further characterize an established murine model of prenatal infection that is based on maternal administration of the viral mimic polyriboinosinic-polyribocytidilic acid [Poly(I:C)], focusing on different aspects of the relationship between altered neurodevelopment and psychiatric disease. First, I will give an overview of the state of the art regarding the association between prenatal infection and different neurodevelopmental illnesses as identified by human epidemiological studies, and then I will present our preclinical results obtained in an experimental model system of prenatal immune activation

Genome-wide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders

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 polyriboinosinic-polyribocytidylic acid 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 polymerase chain reaction analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. Gene ontology 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 gamma-aminobutyric acidergic differentiation and signaling (e.g., Dlx1, Lhx5, Lhx8), Wnt signaling (Wnt3, Wnt8a, Wnt7b), and neural development (e.g., Efnb3, Mid1, Nlgn1, Nrxn2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring\u2019s 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

Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation

Prenatal exposure to infectious and/or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components. Recent research using animal models suggests that maternal immune activation (MIA) can induce transgenerational effects on brain and behavior, possibly through epigenetic mechanisms. Using a mouse model of MIA that is based on gestational treatment with the viral mimeticpoly(I:C) (=polyriboinosinic-polyribocytidilicacid), the present study explored whether the transgenerational effects of MIA are extendable to dopaminergic dysfunctions. We show that the direct descendants born to poly(I:C)-treated mothers display signs of hyperdopaminergia, as manifested by a potentiated sensitivity to the locomotor-stimulating effects of amphetamine (Amph) and increased expression of tyrosine hydroxylase (Th) in the adult ventral midbrain. In stark contrast, second- and third-generation offspring of MIA-exposed ancestors displayed blunted locomotor responses to Amph and reduced expression ofTh. Furthermore, we found increased DNA methylation at the promoter region of the dopamine-specifying factor, nuclear receptor-related 1 protein (Nurr1), in the sperm of first-generation MIA offspring and in the ventral midbrain of second-generation offspring of MIA-exposed ancestors. The latter effect was further accompanied by reduced mRNA levels of Nurr1 in this brain region. Together, our results suggest that MIA has the potential to modify dopaminergic functions across multiple generations with opposite effects in the direct descendants and their progeny. The presence of altered DNA methylation in the sperm of MIA-exposed offspring highlights the possibility that epigenetic processes in the male germline play a role in the transgenerational effects of MIA.Therapeutic cell differentiatio

Genome-wide transcriptional profiling and structural magnetic resonance imaging in the maternal immune activation model of neurodevelopmental disorders

Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, including schizophrenia and autism. The molecular processes underlying this pathological association, however, are only partially understood. Here, we combined unbiased genome-wide transcriptional profiling with follow-up epigenetic analyses and structural magnetic resonance imaging to explore convergent molecular and neuromorphological alterations in corticostriatal areas of adult offspring exposed to prenatal immune activation. Genome-wide transcriptional profiling revealed that prenatal immune activation caused a differential expression of 116 and 251 genes in the medial prefrontal cortex and nucleus accumbens, respectively. A large part of genes that were commonly affected in both brain areas were related to myelin functionality and stability. Subsequent epigenetic analyses indicated that altered DNA methylation of promoter regions might contribute to the differential expression of myelin-related genes. Quantitative relaxometry comparing T1, T2, and myelin water fraction revealed sparse increases in T1 relaxation times and consistent reductions in T2 relaxation times. Together, our multi-system approach demonstrates that prenatal viral-like immune activation causes myelin-related transcriptional and epigenetic changes in corticostriatal areas. Even though these abnormalities do not seem to be associated with overt white matter reduction, they may provide a molecular mechanism whereby prenatal infection can impair myelin functionality and stability

Refining Treatment Planning in STereotactic Arrhythmia Radioablation (STAR): Benchmark Results and Consensus Statement from the STOPSTORM.eu Consortium.

BACKGROUND AND PURPOSE STereotactic Arrhythmia Radioablation (STAR) showed promising results in patients with refractory ventricular tachycardia (VT). However, clinical data is scarce and heterogeneous. The STOPSTORM.eu consortium was established to investigate and harmonize STAR in Europe. The primary goal of this benchmark study was to investigate current treatment planning practice within the STOPSTORM project as a baseline for future harmonization. METHODS Planning target volumes (PTV) overlapping extra-cardiac organs-at-risk and/or cardiac substructures were generated for three STAR cases. Participating centers were asked to create single fraction treatment plans with 25 Gy dose prescription based on in-house clinical practice. All treatment plans were reviewed by an expert panel and quantitative crowd knowledge-based analysis was performed with independent software using descriptive statistics for ICRU report 91 relevant parameters and crowd dose-volume-histograms. Thereafter, treatment planning consensus statements were established using a dual-stage voting process. RESULTS Twenty centers submitted 67 treatment plans for this study. In most plans (75%) Intensity Modulated Arc Therapy (IMAT) with 6 MV flattening-filter-free beams was used. Dose prescription was mainly based on PTV D95% (49%) or D96-100% (19%). Many participants preferred to spare close extra-cardiac organs-at-risk (75%) and cardiac substructures (50%) by PTV coverage reduction. PTV D0.035cm3 ranged 25.5-34.6 Gy, demonstrating a large variety of dose inhomogeneity. Estimated treatment times without motion compensation or setup ranged 2-80 minutes. For the consensus statements, strong agreement was reached for beam technique planning, dose calculation, prescription methods and trade-offs between target and extra-cardiac critical structures. No agreement was reached on cardiac substructure dose limitations and on desired dose inhomogeneity in the target. CONCLUSION This STOPSTORM multi-center treatment planning benchmark study showed strong agreement on several aspects of STAR treatment planning, but also revealed disagreement on others. To standardize and harmonize STAR in the future, consensus statements were established, however clinical data is urgently needed for actionable guidelines for treatment planning

Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

© The Author(s) 2016. Maternal infection during pregnancy increases the risk of offspring developing schizophrenia later in life. Similarly, animal models of maternal immune activation (MIA) induce behavioural and anatomical disturbances consistent with a schizophrenia-like phenotype in offspring. Notably, cognitive impairments in tasks dependent on the prefrontal cortex (PFC) are observed in humans with schizophrenia and in offspring after MIA during pregnancy. Recent studies of post-mortem tissue from individuals with schizophrenia revealed deficits in extracellular matrix structures called perineuronal nets (PNNs), particularly in PFC. Given these findings, we examined PNNs over the course of development in a well-characterized rat model of MIA using polyinosinic-polycytidylic acid (polyI:C). We found selective reductions of PNNs in the PFC of polyI:C offspring which did not manifest until early adulthood. These deficits were not associated with changes in parvalbumin cell density, but a decrease in the percentage of parvalbumin cells surrounded by a PNN. Developmental expression of PNNs was also significantly altered in the amygdala of polyI:C offspring. Our results indicate MIA causes region specific developmental abnormalities in PNNs in the PFC of offspring. These findings confirm the polyI:C model replicates neuropathological alterations associated with schizophrenia and may identify novel mechanisms for cognitive and emotional dysfunction in the disorder