scholarly journals Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: an integrated neuroimaging, behavioural, and transcriptional study

2020 ◽  
Author(s):  
Elisa Guma ◽  
Pedro Bordignon ◽  
Gabriel Allan Devenyi ◽  
Daniel Gallino ◽  
Chloe Anastassiadis ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Dorsal Hippocampus ◽  
Early Adulthood ◽  
Sensorimotor Gating ◽  
Cingulate Cortex ◽  
Late Gestation ◽  
Anterior Cingulate ◽  
Poly I:C ◽  
Maternal Immune Activation

Prenatal maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders. How gestational timing of MIA-exposure differentially impacts downstream development remains unclear. Here, we characterize neurodevelopmental trajectories of mice exposed to MIA induced by poly I:C either early (gestational day [GD]9) or late (GD17) in gestation using longitudinal structural magnetic resonance imaging from weaning to adulthood. Early MIA-exposure associated with accelerated brain volume increases in adolescence/early-adulthood that normalized in later adulthood, in regions including the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety, stereotypic, and sensorimotor gating behaviours observed in adolescence normalized in adulthood. In contrast, MIA-exposure in late gestation had less impact on anatomical and behavioural profiles. Using a multivariate technique to relate imaging and behavioural variables for the time of greatest alteration, i.e. adolescence/early adulthood, we demonstrate that variation in anxiety, social, and sensorimotor gating associates significantly with volume of regions including the dorsal and ventral hippocampus, and anterior cingulate cortex. Using RNA sequencing to explore the molecular underpinnings of region-specific alterations in early MIA-exposed mice in adolescence, we observed the most transcriptional changes in the dorsal hippocampus, with regulated genes enriched for fibroblast growth factor regulation, autistic behaviours, inflammatory pathways, and microRNA regulation. This indicates that MIA in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders. Our findings demonstrate the power of an integrated hypothesis- and data-driven approach in linking brain-behavioural alterations to the transcriptome to understand how MIA confers risk for major mental illness.

scholarly journals Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
◽  
Alexandra Lister
Keyword(s):  
Serotonin Transporter ◽  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Allelic Variation ◽  
Autism Spectrum ◽  
Poly I:C ◽  
Supporting Evidence ◽  
Maternal Immune Activation ◽  
Behavioural Effects ◽  
The Impact

<p>Maternal Immune Activation (MIA) during early pregnancy is an established risk factor for the occurrence of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and schizophrenia (SCZ) in offspring. Serotonin signalling is also implicated in both ASD and SCZ, in conjunction with a known and extensive influence in neural development. Using a Wistar serotonin transporter (SERT) knockout model to mimic allelic variation in the human serotonin transporter promoter (5‐HTTLPR), this research investigates the impact of full or reduced SERT function on the effect of poly I:C-induced MIA in offspring. Experimental design focuses on ultrasonic vocalisation communication in postnatal day (PND) 7 offspring, followed by genetic expression of the Rac1/Kal7/Disc1 signalosome pathway at PND21 previously implicated in SCZ pathology. Results from behavioural analysis of pups indicate a statistically significant increase in calling and call complexity in pups heterozygous for the SERT (SERT HET) compared to wildtype (WT). When separated by sex, this trend remains consistent however only reaches significance in male offspring. Male SERT HET pups also a significant treatment effect in call complexity, and a significant genotype/treatment interaction which suggests an increased susceptibility to MIA-induced behavioural effects. Additionally, poly I:C exposed pups show increased expression of Disc1, supporting evidence that this pathway may be affected in neurodevelopmental disorders. No genotype and sex effects were observed in signalosome expression; however, this study may be too underpowered to detect these effects. These results suggest that differences between sex and SERT genotype in offspring may modulate the behavioural effects of MIA in rodent models of NDD, with more study required to assess these differences in a molecular context. Furthermore, this study aims to address the overall inconsistency and misrepresentation of statistical methods in MIA models by employing MIA validation tests and linear mixed modelling to account for litter variation. In summary, the research presented in this thesis reports initial evidence suggesting SERT genotype may influence the effect of MIA, however further research is necessary to characterise the effect of genotype on MIA challenge during gestation.</p>

scholarly journals Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
◽  
Alexandra Lister
Keyword(s):  
Serotonin Transporter ◽  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Allelic Variation ◽  
Autism Spectrum ◽  
Poly I:C ◽  
Supporting Evidence ◽  
Maternal Immune Activation ◽  
Behavioural Effects ◽  
The Impact

<p>Maternal Immune Activation (MIA) during early pregnancy is an established risk factor for the occurrence of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and schizophrenia (SCZ) in offspring. Serotonin signalling is also implicated in both ASD and SCZ, in conjunction with a known and extensive influence in neural development. Using a Wistar serotonin transporter (SERT) knockout model to mimic allelic variation in the human serotonin transporter promoter (5‐HTTLPR), this research investigates the impact of full or reduced SERT function on the effect of poly I:C-induced MIA in offspring. Experimental design focuses on ultrasonic vocalisation communication in postnatal day (PND) 7 offspring, followed by genetic expression of the Rac1/Kal7/Disc1 signalosome pathway at PND21 previously implicated in SCZ pathology. Results from behavioural analysis of pups indicate a statistically significant increase in calling and call complexity in pups heterozygous for the SERT (SERT HET) compared to wildtype (WT). When separated by sex, this trend remains consistent however only reaches significance in male offspring. Male SERT HET pups also a significant treatment effect in call complexity, and a significant genotype/treatment interaction which suggests an increased susceptibility to MIA-induced behavioural effects. Additionally, poly I:C exposed pups show increased expression of Disc1, supporting evidence that this pathway may be affected in neurodevelopmental disorders. No genotype and sex effects were observed in signalosome expression; however, this study may be too underpowered to detect these effects. These results suggest that differences between sex and SERT genotype in offspring may modulate the behavioural effects of MIA in rodent models of NDD, with more study required to assess these differences in a molecular context. Furthermore, this study aims to address the overall inconsistency and misrepresentation of statistical methods in MIA models by employing MIA validation tests and linear mixed modelling to account for litter variation. In summary, the research presented in this thesis reports initial evidence suggesting SERT genotype may influence the effect of MIA, however further research is necessary to characterise the effect of genotype on MIA challenge during gestation.</p>

scholarly journals M180. SUSCEPTIBILITY AND RESILIENCE IN A MOUSE MODEL OF MATERNAL IMMUNE ACTIVATION

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S204-S205
Author(s):  
Flavia Müller ◽  
Joseph Scarborough ◽  
Juliet Richetto ◽  
Sina Schalbetter ◽  
Ulrike Weber-Stadlbauer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Immune Activation ◽  
Psychotic Disorders ◽  
Sensorimotor Gating ◽  
Epidemiological Studies ◽  
Poly I:C ◽  
Behavioral Testing ◽  
Experimental Conditions ◽  
Maternal Immune Activation ◽  
Mitochondrial Functions

Abstract Background Epidemiological studies over the past decades have repeatedly implicated maternal immune activation (MIA) in the etiology of psychiatric illnesses, including schizophrenia and related psychotic disorders. Not all offspring exposed to MIA, however, develop overt pathologies, suggesting that some are susceptible while others are resilient to MIA. To elucidate susceptibility and resilience in MIA, we used a mouse model that is based on prenatal exposure to the viral mimic poly(I:C). Methods Poly(I:C)-based MIA was induced in C57BL6/N mice on gestation day 12. Control dams received vehicle solution only. Offspring of poly(I:C)- or vehicle-exposed dams were subjected to a comprehensive behavioral testing battery when they reached adulthood (12 weeks of age onwards). Next-generation mRNA sequencing and gene pathway analyses were conducted after behavioral testing to explore the molecular correlates of resilience and susceptibility to MIA. Results Behavioral characterization coupled with unbiased TwoStep cluster analysis of a large number offspring (N &gt;150) revealed that offspring exposed to MIA could be stratified into susceptible and resilient subgroups. While the former was characterized by deficits in social interaction, sensorimotor gating, and working memory, the behavioral profile of the latter was indistinguishable from control offspring. Susceptible and resilient MIA offspring were also dissociable by the presence of distinct molecular profiles in cortical and subcortical brain areas. In the medial prefrontal cortex, susceptible MIA offspring displayed a more profound deregulation of genes relevant for oxidative phosphorylation and mitochondrial functions than resilient MIA offspring. In the amygdala, the susceptible and resilient offspring differed in gene transcription pertinent to opioid signaling, DARPP-32 signaling, and G protein-coupled receptor signaling. Discussion Our data show that MIA can result in substantial phenotypic and transcriptomic variability even in the context of genetic homogeneity and under identical experimental conditions. If extended further, our model system may help to explain why only a subgroup of offspring exposed to MIA develops overt neurodevelopmental sequelae.

scholarly journals GABAergic malfunction underlying maternal immune activation-induced social deficits

2018 ◽  
Author(s):  
Kazuki Okamoto ◽  
Natsuko Hitora-Imamura ◽  
Hiroyuki Hioki ◽  
Yuji Ikegaya
Keyword(s):  
Immune Activation ◽  
Pyramidal Cells ◽  
Social Behaviors ◽  
Underlying Mechanism ◽  
Autism Spectrum ◽  
Anterior Cingulate ◽  
Poly I:C ◽  
Social Deficits ◽  
Social Ability ◽  
Maternal Immune Activation

AbstractSocial deficits are one of the major symptoms of psychiatric disorders, including autism spectrum disorders (ASDs) and schizophrenia. However, the underlying mechanism remains ill-defined. Here, we focused on the anterior cingulate cortex (ACC), a brain region that is related to social behaviors, of mice that received poly(I:C)-induced maternal immune activation. Using whole-cell patch clamp recordings, we found that layer 2/3 pyramidal cells were hyperactive in acute ACC slices prepared from poly(I:C)-treated mice compared to those from saline-treated mice. The hyperexcitation was associated with a reduction in inhibitory synapse activity. Local injection of the GABAA receptor enhancer clonazepam into the ACC of poly(I:C)-treated mice restored the social behaviors of the mice. These results suggest that the balanced excitability of ACC neurons is essential for social ability.

scholarly journals Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

2020 ◽  
Author(s):  
Flavia S. Mueller ◽  
Joseph Scarborough ◽  
Sina M. Schalbetter ◽  
Juliet Richetto ◽  
Eugene Kim ◽  
...  
Keyword(s):  
Immune Activation ◽  
Ex Vivo ◽  
Sensorimotor Gating ◽  
Brain Regions ◽  
Brain Network ◽  
Poly I:C ◽  
Psychiatric Research ◽  
Maternal Immune Activation ◽  
Peripheral Production ◽  
And Control

AbstractInfectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.

scholarly journals The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

2021 ◽  
Vol 11 (3) ◽  
pp. 344
Author(s):  
Kinga Gzielo ◽  
Agnieszka Potasiewicz ◽  
Ewa Litwa ◽  
Diana Piotrowska ◽  
Piotr Popik ◽  
...  
Keyword(s):  
Immune Activation ◽  
Social Play ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Rats ◽  
Poly I:C ◽  
Maternal Immune Activation ◽  
Increased Risk ◽  
Adolescent Rats ◽  
The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

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