Modeling Autism-Related Disorders in Mice with Maternal Immune Activation (MIA)

Lammert, Catherine R.; Lukens, John R.

doi:10.1007/978-1-4939-9167-9_20

Cited by 35 publications

(21 citation statements)

References 26 publications

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“…The recording was analyzed with the UltraVox software (Noldus Information Technology). The USVs between 25 and 125 kHz were analyzed after excluding the background noise that was , 0.02 ms (Lammert and Lukens, 2019).…”

Section: Methodsmentioning

confidence: 99%

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Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects

Chen

Mandhani

et al. 2020

J. Neurosci.

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Growing evidence suggests that early-life interactions among genetic, immune, and environment factors may modulate neurodevelopment and cause psycho-cognitive deficits. Maternal immune activation (MIA) induces autism-like behaviors in offspring, but how it interplays with perinatal brain injury (especially birth asphyxia or hypoxia ischemia [HI]) is unclear. Herein we compared the effects of MIA (injection of poly[I:C] to dam at gestational day 12.5), HI at postnatal day 10, and the combined MIA/HI insult in murine offspring of both sexes. We found that MIA induced autistic-like behaviors without microglial activation but amplified post-HI NFjB signaling, pro-inflammatory responses, and brain injury in offspring. Conversely, HI neither provoked autistic-like behaviors nor concealed them in the MIA offspring. Instead, the dual MIA/HI insult added autistic-like behaviors with diminished synaptic density and reduction of autism-related PSD-95 and Homer-1 in the hippocampus, which were missing in the singular MIA or HI insult. Further, the dual MIA/HI insult enhanced the brain influx of Otx2-positive monocytes that are associated with an increase of perineuronal net-enwrapped parvalbumin neurons. Using CCR2-CreER mice to distinguish monocytes from the resident microglia, we found that the monocytic infiltrates gradually adopted a ramified morphology and expressed the microglial signature genes (Tmem119, P2RY12, and Sall1) in post-MIA/HI brains, with some continuing to express the proinflammatory cytokine TNFa. Finally, genetic or pharmacological obstruction of monocytic influx significantly reduced perineuronal net-enwrapped parvalbumin neurons and autistic-like behaviors in MIA/HI offspring. Together, these results suggest a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmental defects.

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Section: Methodsmentioning

confidence: 99%

“…After each testing period, the marbles were cleaned with 70% ethanol. All procedures were essentially the same as previously described (Lammert and Lukens, 2019).…”

Section: Methodsmentioning

confidence: 99%

Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects

Chen

Mandhani

et al. 2020

J. Neurosci.

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“…Maternal immune activation (MIA) during pregnancy is recognized as an etiological risk factor for various psychiatric and neurological disorders in offspring 1 . The highly orchestrated processes of neural development start with the proliferation and migration of glia and neurons followed by programmed cell death, the formation of synapses, myelination, and the establishment of neuronal circuits 2 .…”

Section: Introductionmentioning

confidence: 99%

Maternal immune activation generates anxiety in offspring: A translational meta-analysis

2021

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Maternal immune activation (MIA) during pregnancy is recognized as an etiological risk factor for various psychiatric disorders, such as schizophrenia, major depressive disorder, and autism. Prenatal immune challenge may serve as a “disease primer” for alteration of the trajectory of fetal brain development that, in combination with other genetic and environmental factors, may ultimately result in the emergence of different psychiatric conditions. However, the association between MIA and an offspring’s chance of developing anxiety disorders is less clear. To evaluate the effect of MIA on offspring anxiety, a systematic review and meta-analysis of the preclinical literature was conducted. We performed a systematic search of the PubMed, Web of Science, PsycINFO, and Cochrane Library electronic databases using the PRISMA and World Health Organization (WHO) methodologies for systematic reviews. Studies that investigated whether MIA during pregnancy could cause anxiety symptoms in rodent offspring were included. Overall, the meta-analysis showed that MIA induced anxiety behavior in offspring. The studies provide strong evidence that prenatal immune activation impacts specific molecular targets and synapse formation and function and induces an imbalance in neurotransmission that could be related to the generation of anxiety in offspring. Future research should further explore the role of MIA in anxiety endophenotypes. According to this meta-analysis, MIA plays an important role in the pathophysiological mechanisms of anxiety disorders and is a promising therapeutic target.

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“…Mice were treated similarly as previously described to trigger robust MIA [11,102]. Mice were mated overnight and the presence of a vaginal plug was designated as E0.5.…”

Section: Maternal Immune Activationmentioning

confidence: 99%

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

Frost

Lammert

et al. 2020

RNA Biology

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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, 5ʹ tRNA halves from tRNA Gly , tRNA Glu , tRNA Val and tRNA Lys 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 maternalfetal 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 5ʹ 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.

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Modeling Autism-Related Disorders in Mice with Maternal Immune Activation (MIA)

Cited by 35 publications

References 26 publications

Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects

Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects

Maternal immune activation generates anxiety in offspring: A translational meta-analysis

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

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