Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Guma, Elisa; Bordeleau, Maude; Ibáñez, Fernando González; Picard, Katherine; Snook, Emily; Desrosiers-Grégoire, Gabriel; Spring, Shoshana; Lerch, Jason P.; Nieman, Brian J.; Devenyi, Gabriel A.; Tremblay, Marie‐Ève; Chakravarty, M. Mallar

doi:10.1073/pnas.2114545119

Cited by 28 publications

(26 citation statements)

References 83 publications

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“…While dark microglia were previously reported at adulthood in several mouse models of pathology (e.g., prenatal and maternal immune activation, middle-aged APP-PS1, chronic stress, CX3CR1 knockout, R6/2 model of Huntington's disease; [64,78,94,105,106]), their presence in the human brain had yet to be reported. We observed dark cells possessing ultrastructural features of dark microglia in the hippocampal head of post-mortem brain samples from a 49-year-old man and in the parahippocampal gyrus from an 81-year-old woman (both with a post-mortem interval of 18 h).…”

Section: Dark Microglia Are Found In Human Post-mortem Brain Samples ...mentioning

confidence: 99%

Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer’s disease pathology and in human post-mortem brain samples

St‐Pierre

Carrier

Ibáñez

et al. 2022

J Neuroinflammation

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A diverse heterogeneity of microglial cells was previously described in Alzheimer’s disease (AD) pathology, including dark microglia, a state characterized by ultrastructural markers of cellular stress. To provide novel insights into the roles of dark microglia during aging in the context of AD pathology, we performed a quantitative density and ultrastructural analysis of these cells using high-throughput scanning electron microscopy in the ventral hippocampus CA1 stratum lacunosum-moleculare of 20-month-old APP-PS1 vs C57BL/6J male mice. The density of dark microglia was significantly higher in APP-PS1 vs C57BL/6J mice, with these cells accounting for nearly half of all microglia observed near amyloid-beta (Aβ) plaques. This dark microglial state interacted more with dystrophic neurites compared to other APP-PS1 microglia and possessed glycogen granules, associated with a metabolic shift toward glycolysis, which provides the first ultrastructural evidence of their presence in microglia. Dark microglia were further observed in aging human post-mortem brain samples showing similar ultrastructural features as in mouse. Overall, our results provide a quantitative ultrastructural characterization of a microglial state associated with cellular stress (i.e., dark microglia) that is primarily restricted near Aβ plaques and dystrophic neurites. The presence of this microglial state in the aging human post-mortem brain is further revealed.

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Section: Dark Microglia Are Found In Human Post-mortem Brain Samples ...mentioning

confidence: 99%

Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer’s disease pathology and in human post-mortem brain samples

St‐Pierre

Carrier

Ibáñez

et al. 2022

J Neuroinflammation

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“…More recent studies continue to highlight the importance of prenatal timing in poly I:C‐induced MIA models 45,196,197 . A central theme in these studies is the temporally regulated impairment of GABAergic interneuron subtypes.…”

Section: Future Perspectives and Considerations For Mia Modelingmentioning

confidence: 99%

At the crux of maternal immune activation: Viruses, microglia, microbes, and IL‐17A

Otero

Antonson

2022

Immunological Reviews

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Summary Inflammation during prenatal development can be detrimental to neurodevelopmental processes, increasing the risk of neuropsychiatric disorders. Prenatal exposure to maternal viral infection during pregnancy is a leading environmental risk factor for manifestation of these disorders. Preclinical animal models of maternal immune activation (MIA), established to investigate this link, have revealed common immune and microbial signaling pathways that link mother and fetus and set the tone for prenatal neurodevelopment. In particular, maternal intestinal T helper 17 cells, educated by endogenous microbes, appear to be key drivers of effector IL‐17A signals capable of reaching the fetal brain and causing neuropathologies. Fetal microglial cells are particularly sensitive to maternally derived inflammatory and microbial signals, and they shift their functional phenotype in response to MIA. Resulting cortical malformations and miswired interneuron circuits cause aberrant offspring behaviors that recapitulate core symptoms of human neurodevelopmental disorders. Still, the popular use of “sterile” immunostimulants to initiate MIA has limited translation to the clinic, as these stimulants fail to capture biologically relevant innate and adaptive inflammatory sequelae induced by live pathogen infection. Thus, there is a need for more translatable MIA models, with a focus on relevant pathogens like seasonal influenza viruses.

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“…These studies are further motivated by recent observations that offspring exposed to MIA (modeling the exposure to maternal infection during pregnancy, a known risk factor for neurodevelopmental disorders) show litter-dependent variance in resilience and susceptibility to the risk factor exposure (Mueller et al, 2021). However, our group also demonstrated that the gestational timing of MIA-exposure could further modulate neurodevelopmental outcomes (Guma, do Couto Bordignon, et al, 2021; Guma et al, 2022; Guma, Snook, et al, 2021). At an even more basic level, litter-dependent modulation of body and brain weight have been reported using linear and linear mixed-effect models; these effects are further affected by sex (Golub & Sobin, 2020; Jiménez & Zylka, 2021).…”

Section: Introductionmentioning

confidence: 68%

Examining Litter Specific Variability in Mice and its Impact on Neurodevelopmental Studies

Valiquette

Guma

Cupo

et al. 2022

Preprint

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Our current understanding of litter variability in neurodevelopmental studies using mouse may limit translation of neuroscientific findings. Higher variance of measures across litters than within, often termed intra-litter likeness, may be attributable to pre- and postnatal environment. This study aimed to assess the litter-effect within behavioral assessments (2 timepoints), and anatomy using T1-weighted magnetic resonance images (4 timepoints) across 72 brain region volumes (36 C57bl/6J inbred mice; 7 litters: 19F/17M). Between-litter comparisons of brain and behavioral measures and their associations were evaluated using univariate and multivariate techniques. A power analysis using simulation methods was then performed modeling neurodevelopment and evaluating trade-offs between number-of-litters, mice-per-litter, and sample size. Our results show litter-specific developmental effects, from the adolescent period to adulthood for brain structure volumes and behaviors, and their associations in adulthood. Our power simulation analysis results suggest increasing the number-of-litters in experimental design to achieve the smallest total sample size for detecting different rates of change in specific brain regions. Our results also demonstrate how litter-specific effects may influence development and that increasing the litters to the total sample size ratio should be strongly considered when designing neurodevelopmental studies.

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Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Cited by 28 publications

References 83 publications

Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer’s disease pathology and in human post-mortem brain samples

Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer’s disease pathology and in human post-mortem brain samples

At the crux of maternal immune activation: Viruses, microglia, microbes, and IL‐17A

Examining Litter Specific Variability in Mice and its Impact on Neurodevelopmental Studies

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