Maternal immune activation induces methylation changes in schizophrenia genes

Abstract Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery γ-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14–15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth.

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Increased RNA editing in maternal immune activation model of neurodevelopmental disease

Nature Communications ◽

10.1038/s41467-020-19048-6 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Hadas Tsivion-Visbord ◽

Eli Kopel ◽

Ariel Feiglin ◽

Tamar Sofer ◽

Ran Barzilay ◽

...

Keyword(s):

Brain Development ◽

Rna Editing ◽

Immune Activation ◽

Critical Time ◽

Adult Brain ◽

Behavioral Deficits ◽

Neurodevelopmental Disease ◽

Maternal Immune Activation ◽

Transcriptional Changes ◽

Mouse Fetuses

Abstract 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 and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.

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The development of animal models for autism: A gene-environment approach

10.26686/wgtn.17019029.v1 ◽

2021 ◽

Author(s):

◽

Peter Ranger

Keyword(s):

Animal Models ◽

Prenatal Exposure ◽

Environmental Risk ◽

Rat Model ◽

Immune Activation ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Maternal Immune Activation ◽

Gene Environment ◽

Social Communicative

<p>Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by social, communicative, and behavioural deficits. Despite decades of research in this field, effective pharmacological treatments for ASD are still lacking and better animal models for this disorder are urgently needed. Although it is now well understood that both genetic and environmental influences play a role in the aetiology of ASD, most existing animal models for this disorder only take into account one of these aetiological contributors and have largely ignored investigating an interaction. The main aim of this thesis was to develop a novel animal model for ASD that demonstrated higher construct validity than traditional models by using a gene-environment approach. To this aim, two previously established environmental risk factor-based models for ASD were each combined with a genetic rat model that mimicked a genotype associated with ASD. Specifically, a maternal immune activation model (modelled via prenatal administration of lipopolysaccharide) and a prenatal exposure to valproate model (modelled via prenatal administration of valproate) were both combined with a serotonin transporter (SERT) knockout rat model. Next, experimental rats were investigated in a variety of paradigms designed to detect behavioural, biochemical, and immunological outcomes related to ASD. This thesis tested the hypothesis that rats with a genetically compromised SERT function would be more vulnerable to the impacts of the two environmental risk factors. Collectively, the data from this thesis show that rats with a genetically compromised SERT function are not more vulnerable to the impacts of a maternal immune activation or prenatal exposure to VPA. In fact, at least with regards to prenatal exposure to valproate, rats with a compromised SERT function actually appeared more resilient to ASD-like outcomes.</p>

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Cortical spreading depression-induced preconditioning in mouse neocortex is lamina specific

Journal of Neurophysiology ◽

10.1152/jn.00855.2011 ◽

2013 ◽

Vol 109 (12) ◽

pp. 2923-2936 ◽

Cited By ~ 8

Author(s):

Helen M. Gniel ◽

Rosemary L. Martin

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Pyramidal Neurons ◽

Brain Slices ◽

Glucose Deprivation ◽

Time Frame ◽

Degree Of Protection ◽

Equilibrative Nucleoside Transporters ◽

A Cell ◽

Layer V

Cortical spreading depression (CSD) is able to confer neuroprotection when delivered at least 1 day in advance of an ischemic event. However, its ability to confer neuroprotection in a more immediate time frame has not previously been investigated. Here we have used mouse neocortical brain slices to study the effects of repeated episodes of CSD in layer V and layer II/III pyramidal neurons. In layer V, CSD evoked at 15-min intervals caused successively smaller membrane depolarizations and increases in intracellular calcium compared with the response to the first CSD. With an inter-CSD interval of 30 min this preconditioning effect was much less marked, indicating that preconditioning lasts between 15 and 30 min. A single episode of CSD also provided a degree of protection in oxygen-glucose deprivation (OGD) by significantly lengthening the time a cell could withstand OGD before anoxic depolarization occurred. In layer II/III pyramidal neurons no preconditioning by CSD on subsequent episodes of CSD was observed, demonstrating that the response of pyramidal neurons to repeated CSD is lamina specific. The A1 receptor antagonist 8-cyclopentyl theophylline (8-CPT) reduced the layer V preconditioning in a concentration-related manner. Inhibition of extracellular formation of adenosine by blocking ecto-5′-nucleotidase with α,β-methyleneadenosine 5′-diphosphate prevented preconditioning in most but not all cells. Block of equilibrative nucleoside transporters 1 and 2 with dipyramidole alone or in combination with 6-[(4-nitrobenzyl)thio]-9-β-d-ribofuranosylpurine also prevented preconditioning in some but not all cells. These data provide evidence that rapid preconditioning of one CSD by another is primarily mediated by adenosine.

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The development of animal models for autism: A gene-environment approach

10.26686/wgtn.17019029 ◽

2021 ◽

Author(s):

◽

Peter Ranger

Keyword(s):

Animal Models ◽

Prenatal Exposure ◽

Environmental Risk ◽

Rat Model ◽

Immune Activation ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Maternal Immune Activation ◽

Gene Environment ◽

Social Communicative

<p>Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by social, communicative, and behavioural deficits. Despite decades of research in this field, effective pharmacological treatments for ASD are still lacking and better animal models for this disorder are urgently needed. Although it is now well understood that both genetic and environmental influences play a role in the aetiology of ASD, most existing animal models for this disorder only take into account one of these aetiological contributors and have largely ignored investigating an interaction. The main aim of this thesis was to develop a novel animal model for ASD that demonstrated higher construct validity than traditional models by using a gene-environment approach. To this aim, two previously established environmental risk factor-based models for ASD were each combined with a genetic rat model that mimicked a genotype associated with ASD. Specifically, a maternal immune activation model (modelled via prenatal administration of lipopolysaccharide) and a prenatal exposure to valproate model (modelled via prenatal administration of valproate) were both combined with a serotonin transporter (SERT) knockout rat model. Next, experimental rats were investigated in a variety of paradigms designed to detect behavioural, biochemical, and immunological outcomes related to ASD. This thesis tested the hypothesis that rats with a genetically compromised SERT function would be more vulnerable to the impacts of the two environmental risk factors. Collectively, the data from this thesis show that rats with a genetically compromised SERT function are not more vulnerable to the impacts of a maternal immune activation or prenatal exposure to VPA. In fact, at least with regards to prenatal exposure to valproate, rats with a compromised SERT function actually appeared more resilient to ASD-like outcomes.</p>

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