Increased RNA editing in maternal immune activation model of neurodevelopmental disease.
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ABSTRACT:
SUBMITTER: Tsivion-Visbord H
PROVIDER: S-EPMC7567798 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Increased RNA editing in maternal immune activation model of neurodevelopmental disease.
Tsivion-Visbord Hadas H Kopel Eli E Feiglin Ariel A Sofer Tamar T Barzilay Ran R Ben-Zur Tali T Yaron Orly O Offen Daniel D Levanon Erez Y EY
Nature communications 20201016 1
The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral ...[more]
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Project description:Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment.
| S-EPMC4955953 | biostudies-literature
Project description:Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.
| S-EPMC6452650 | biostudies-literature
Project description:The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls. We also measured these markers in midbrain of mice exposed to maternal immune activation (MIA) during pregnancy, an established risk factor for schizophrenia and other psychiatric disorders. We found diagnostic increases in SERPINA3, TNFα, IL1β, IL6, and IL6ST transcripts in schizophrenia compared with controls (p < 0.02-0.001). The diagnostic differences in these immune markers were accounted for by a subgroup of schizophrenia cases (~ 45%, 13/28) showing high immune status. Consistent with the human cohort, we identified increased expression of immune markers in the midbrain of adult MIA offspring (SERPINA3, TNFα, and IL1β mRNAs, all p ≤ 0.01), which was driven by a subset of MIA offspring (~ 40%, 13/32) with high immune status. There were no diagnostic (human cohort) or group-wise (mouse cohort) differences in cellular markers indexing the density and/or morphology of microglia or astrocytes, but an increase in the transcription of microglial and astrocytic markers in schizophrenia cases and MIA offspring with high inflammation. These data demonstrate that immune-related changes in schizophrenia extend to dopaminergic areas of the midbrain and exist in the absence of changes in microglial cell number, but with putative evidence of microglial and astrocytic activation in the high immune subgroup. MIA may be one of the contributing factors underlying persistent neuroimmune changes in the midbrain of people with schizophrenia.
| S-EPMC7910216 | biostudies-literature
Project description:Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the "two-hit" hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the "second hit" in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.
| S-EPMC7913889 | biostudies-literature
Project description:Background and objectivesThe neurodevelopment of the offspring is suggested to be influenced by the maternal immune system's responses throughout pregnancy, which in turn is also vulnerable to maternal psychosocial stress conditions. Therefore, our main goal was to investigate whether maternal peripheral immunological biomarkers (IB) during two stages of gestation are associated with distinct neurodevelopmental trajectories in the first two years of life. As a second goal, we also explored the association between maternal distal (childhood) and proximal (gestation) stressful experiences and the immunological markers assessed during pregnancy.MethodsMaternal childhood trauma, depressive and anxiety symptoms, and peripheral IB (IFNγ, IL-10, IL1β, IL6, IL8, TNFα, EGF, IL13, IL17, IL1Ra and IL4) were measured at baseline (8-16 weeks of pregnancy) and at 30 weeks of pregnancy in 160 women. The participants had the blood samples collected from two randomized clinical trials conducted by the same team and methods in the same community. A Principal Component Analysis (PCA) was implemented to create meaningful composite variables that describe the cytokines joint variation. Finally, linear mixed-effects modeling was used to investigate the influence of inflammatory biomarkers, maternal childhood trauma, anxiety, and depressive symptoms on Bayley's III scores trajectories.ResultsThe IB profile during the 3rd trimester of pregnancy predicted the offspring's neurodevelopmental trajectories in the first two years of life. The components derived from PCA were important predictors and captured different immune responses, reflecting both pro- and anti-inflammatory states. Maternal stressful experiences did not correlate with the immunological markers. Although not a reliable predictor alone, maternal psychosocial stress at the 1st trimester of pregnancy interacted with the mother's immune response while predicting the neurodevelopmental scores during the first two years of life.ConclusionsOur results underscore the importance of the maternal immune response during pregnancy in shaping the neurodevelopmental trajectory of the offspring. Additionally, we observed that the maternal distress at the early stages of pregnancy has an incremental effect on the neurodevelopmental outcome but depends upon the immune response.
| S-EPMC11347843 | biostudies-literature
Project description:OBJECTIVE:Adenosine-to-inosine (A-to-I) RNA editing of Alu retroelements is a primate-specific mechanism mediated by adenosine deaminases acting on RNA (ADARs) that diversifies transcriptome by changing selected nucleotides in RNA molecules. We tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA). METHODS:Synovium expression analysis of ADAR1 was investigated in 152 RA patients and 50 controls. Peripheral blood mononuclear cells derived from 14 healthy subjects and 19 patients with active RA at baseline and after 12-week treatment were examined for ADAR1p150 and ADAR1p110 isoform expression by RT-qPCR. RNA editing activity was analysed by AluSx+ Sanger-sequencing of cathepsin S, an extracellular matrix degradation enzyme involved in antigen presentation. RESULTS:ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the blood of active RA patients. Individual nucleotide analysis revealed that A-to-I RNA editing rate was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rate of cathepsin S AluSx+ decreased after treatment only in those patients with good clinical response. Upregulation of the expression and/or activity of the RNA editing machinery were associated with a higher expression of edited Alu-enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5. CONCLUSION:A previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control in RA underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.
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Project description:Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents can be induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic system in the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior cingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, a high affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC of offspring, similar to the neuronal pathology reported in patients with schizophrenia.
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Project description:The developing immune system and central nervous system in the fetus and child are extremely sensitive to both exogenous and endogenous signals. Early immune system programming, leading to changes that can persist over the life course, has been suggested, and other evidence suggests that immune dysregulation in the early developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. The timing of immune dysregulation with respect to gestational age and neurologic development of the fetus may shape the elicited response. This creates a possible sensitive window of programming or vulnerability. This review will explore the effects of maternal prenatal and infant nutritional status (from conception until early childhood) as well as maternal prenatal stress and anxiety on early programming of immune function, and how this might influence neurodevelopment. We will describe fetal immune system development and maternal-fetal immune interactions to provide a better context for understanding the influence of nutrition and stress on the immune system. Finally, we will discuss the implications for prevention of neurodevelopmental disorders, with a focus on nutrition. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether their impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which may contribute to a better understanding of preventative mechanisms. Integrating studies of neurodevelopmental disorders and prenatal exposures with the simultaneous evaluation of neural and immune systems will shed light on mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders and ultimately contribute to the development of primary preventions and early interventions.
| S-EPMC3728489 | biostudies-other
Project description:tRNA-derived small fragments (tRFs) and tRNA halves have emerging functions in different biological pathways, such as regulating gene expression, protein translation, retrotransposon activity, transgenerational epigenetic changes and response to environmental stress. However, small RNAs like tRFs and microRNAs in the maternal-fetal interface during gestation have not been studied extensively. Here we investigated the small RNA composition of mouse placenta/decidua, which represents the interface where the mother communicates with the foetus, to determine whether there are specific differences in tRFs and microRNAs during fetal development and in response to maternal immune activation (MIA). Global tRF expression pattern, just like microRNAs, can distinguish tissue types among placenta/decidua, fetal brain and fetal liver. In particular, 5' tRNA halves from tRNAGly, tRNAGlu, tRNAVal and tRNALys are abundantly expressed in the normal mouse placenta/decidua. Moreover, tRF and microRNA levels in the maternal-fetal interface change dynamically over the course of embryonic development. To see if stress alters non-coding RNA expression at the maternal-fetal interface, we treated pregnant mice with a viral infection mimetic, which has been shown to promote autism-related phenotypes in the offspring. Acute changes in the levels of specific tRFs and microRNAs were observed 3-6 h after MIA and are suppressed thereafter. A group of 5' tRNA halves is down-regulated by MIA, whereas a group of 18-nucleotide tRF-3a is up-regulated. In conclusion, tRFs show tissue-specificity, developmental changes and acute response to environmental stress, opening the possibility of them having a role in the fetal response to MIA.
| S-EPMC7549640 | biostudies-literature
Project description:Prenatal factors influence autism spectrum disorder (ASD) incidence in children and can increase ASD symptoms in offspring of animal models. These may include maternal immune activation (MIA) due to viral or bacterial infection during the first trimesters. Unfortunately, regardless of ASD etiology, existing drugs are poorly effective against core symptoms. For nearly a century a ketogenic diet (KD) has been used to treat seizures, and recent insights into mechanisms of ASD and a growing recognition that immune/inflammatory conditions exacerbate ASD risk has increased interest in KD as a treatment for ASD. Here we studied the effects of KD on core ASD symptoms in offspring exposed to MIA. To produce MIA, pregnant C57Bl/6 mice were injected with the viral mimic polyinosinic-polycytidylic acid; after weaning offspring were fed KD or control diet for three weeks. Consistent with an ASD phenotype of a higher incidence in males, control diet-fed MIA male offspring were not social and exhibited high levels of repetitive self-directed behaviors; female offspring were unaffected. However, KD feeding partially or completely reversed all MIA-induced behavioral abnormalities in males; it had no effect on behavior in females. KD-induced metabolic changes of reduced blood glucose and elevated blood ketones were quantified in offspring of both sexes. Prior work from our laboratory and others demonstrate KDs improve relevant behaviors in several ASD models, and here we demonstrate clear benefits of KD in the MIA model of ASD. Together these studies suggest a broad utility for metabolic therapy in improving core ASD symptoms, and support further research to develop and apply ketogenic and/or metabolic strategies in patients with ASD.
| S-EPMC5293204 | biostudies-literature