Reversing behavioural abnormalities in mice exposed to maternal inflammation

Yim, Yeong Shin; Park, Ashley; Berrios, Janet; Lafourcade, Mathieu; Pascual, Leila M.; Soares, Natalie; Kim, Joo Yeon; Kim, Sangdoo; Kim, Hyun-Ju; Waisman, Ari; Littman, Dan R.; Wickersham, Ian R.; Harnett, Mark T.; Huh, Jun R.; Choi, Gloria B.

doi:10.1038/nature23909

Cited by 256 publications

(175 citation statements)

References 47 publications

(39 reference statements)

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“…Microglia have been reported to sculpt the developing circuits by engulfing and remodeling synapses in an activity-dependent manner 37,38 . Transient perturbations in the development of microglia, such as those induced by the used environmental stressor, maternal immune activation (MIA), have far reaching effects on adult neuronal function and behavior 39,40 that have been linked to mental illness 41 . Moreover, mutations in the C4 gene, a complement component that is required for synapse elimination by microglia 38 , has been linked to schizophrenia 41 .…”

Section: Resultsmentioning

confidence: 99%

Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness

Chini¹,

Lindemann²,

Ja³

et al. 2018

Preprint

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SUMMARYCognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal-hippocampal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Combining in vivo electrophysiology and optogenetics with neuroanatomy and pharmacology in neonatal mice mimicking the dual genetic - environmental etiology of psychiatric disorders, we identified pyramidal neurons in layer II/III of the prefrontal cortex as key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing result from sparser dendritic arborization and lower spine density. Pharmacological modulation of aberrantly hyper-mature microglia rescues morphological, synaptic and functional neuronal deficits and restores the early circuit function. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.HighlightsMice mimicking the etiology of mental illness have dysregulated prefrontal networkStructural and synaptic deficits cause abnormal rate and timing of pyramidal firingWeaker activation of prefrontal circuits results from deficits of pyramidal neuronsRescue of microglial function restores developing prefrontal circuits

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Section: Resultsmentioning

confidence: 99%

Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness

Chini¹,

Lindemann²,

Ja³

et al. 2018

Preprint

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“…Upregulated expression of both IL-17a and TNFα also resulted in autism-like behaviors and deficits in social interaction in MIA-exposed offspring (Choi et al, 2016; Pendyala et al, 2017). Furthermore, upregulated expression of IL-17a and its receptor in the fetal brain may have led to the formation of cortical patches associated with MIA-induced behavioral abnormalities, though the exact mechanism is still unknown (Shin et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

Maternal Exposures Associated with Autism Spectrum Disorder in Jamaican Children

Christian

Samms‐Vaughan

Lee

et al. 2018

J Autism Dev Disord

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with poorly understood etiology. Many maternal exposures during pregnancy and breastfeeding potentially interfere with neurodevelopment. Using data from two age- and sex-matched case-control studies in Jamaica (n = 298 pairs), results of conditional logistic regression analyses suggest that maternal exposures to fever or infection (matched odds ratio (MOR) = 3.12, 95% CI 1.74-5.60), physical trauma (MOR 2.02, 95% CI 1.01-4.05), and oil-based paints (MOR 1.99, 95% CI 1.14-3.46) may be associated with ASD. Additionally, maternal exposure to oil-based paints may modify the relationship between maternal exposure to pesticides and ASD, which deepens our understanding of the association between pesticides and ASD.

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“…This protection was associated with alterations to the gut microbiome of the offspring, resulting in a more “anti-inflammatory” environment. Similarly, the impact of MIA with poly I:C on maternal IL-17a and fetal outcomes was recently demonstrated to depend on the precise microbiota present in the maternal gut [34,35]. In sum, these data point toward an inter-relatedness of various components of the developing nervous and immune systems, environment, and microglial function, and suggest potential mechanisms by which a greater understanding of environmental impacts on glial development and biology might lead to therapeutic benefits in the treatment and prevention of neurological disorders.…”

Section: Building Better Models and Conclusionmentioning

confidence: 99%

Environment matters: microglia function and dysfunction in a changing world

Hanamsagar

Bilbo

2017

Current Opinion in Neurobiology

107

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The immune system is our interface with the environment, and immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy or the early postnatal period, e.g. in response to infection, may disrupt the normal developmental trajectory of microglia and consequently their interactions with neurons, thereby contributing to the risk for neurological disorders. The current article outlines recent findings on the impact of diverse, pervasive environmental challenges, beyond infection, including air pollution and maternal stress; and their impact on microglial development and its broad implications for neural pathologies.

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Reversing behavioural abnormalities in mice exposed to maternal inflammation

Cited by 256 publications

References 47 publications

Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness

Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness

Maternal Exposures Associated with Autism Spectrum Disorder in Jamaican Children

Environment matters: microglia function and dysfunction in a changing world

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