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The role of IL-6 in neurodevelopment after prenatal stress
Open accessAbstract
Prenatal stress exposure is associated with adverse psychiatric outcomes, including autism and ADHD, as well as locomotor and social inhibition and anxiety-like behaviors in animal offspring. Similarly, maternal immune activation also contributes to psychiatric risk and aberrant offspring behavior. The mechanisms underlying these outcomes are not clear. Offspring microglia and the pro-inflammatory cytokine interleukin-6 (IL-6), known to influence microglia, may serve as common mechanisms between prenatal stress and prenatal immune activation. To evaluate the role of prenatal IL-6 in prenatal stress, microglia morphological analyses were conducted at embryonic days 14 (E14), E15, and in adult mice. Offspring microglia and behavior were evaluated after repetitive maternal restraint stress, repetitive maternal IL-6, or maternal IL-6 blockade during stress from E12 onwards. At E14, novel changes in cortical plate embryonic microglia were documented-a greater density of the mutivacuolated morphology. This resulted from either prenatal stress or IL-6 exposure and was prevented by IL-6 blockade during prenatal stress. Prenatal stress also resulted in increased microglia ramification in adult brain, as has been previously shown. As with embryonic microglia, prenatal IL-6 recapitulated prenatal stress-induced changes in adult microglia. Furthermore, prenatal IL-6 was able to recapitulate the delay in GABAergic progenitor migration caused by prenatal stress. However, IL-6 mechanisms were not necessary for this delay, which persisted after prenatal stress despite IL-6 blockade. As we have previously demonstrated, behavioral effects of prenatal stress in offspring, including increased anxiety-like behavior, decreased sociability, and locomotor inhibition, may be related to these GABAergic delays. While adult microglia changes were ameliorated by IL-6 blockade, these behavioral changes were independent of IL-6 mechanisms, similar to GABAergic delays. This and previous work from our laboratory suggests that multiple mechanisms, including GABAergic delays, may underlie prenatal stress-linked deficits.
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“Importantly, increased levels of IL-6 alone recapitulate aspects of ASD pathophysiology [138, 142, 143].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [142]
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“Such regulation may also be altered by activation of microglia cells under stress conditions including MIA and/or in response to increase levels of IL-6 [142].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [142]
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The ASD Living Biology: from cell proliferation to clinical phenotype
Courchesne, E., Pramparo, T., Gazestani, V. H., Lombardo, M. V., Pierce, K., & Lewis, N. E. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0056-y · Cited by 333
Comer, A. L., Carrier, M., Tremblay, M., & Cruz‐Martín, A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00274 · Cited by 212
Gumusoglu, S. B., & Stevens, H. E. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.08.008 · Cited by 216
Self-citationMaternal inflammation and its ramifications on fetal neurodevelopment
Kwon, H., Choi, G. B., & Huh, J. R. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.01.007 · Cited by 204
Zawadzka, A., Cieślik, M., & Adamczyk, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111516 · Cited by 197
Metadata
- Authors
- Gumusoglu, S. B., Fine, R. S., Murray, S. J., Bittle, J. L., & Stevens, H. E.
- Affiliations
- University of Iowa (US)
- Yale University (US)
- Corresponding author
- Stevens, Hanna E.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 65
- Pages
- 274-283
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5537020
- OpenAlex
- W2617644144
- Cited by
- 129
- References
- 79
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 15 · 2023: 14 · 2022: 22 · 2021: 15 · 2020: 12 · 2019: 11 · 2018: 14
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K08MH086812, R25MH077823)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- interleukin-6, prenatal stress, maternal restraint stress, microglia, brain development, maternal immune activation, cortical plate, anxiety-like behavior, sociability, locomotor inhibition, autism spectrum disorder, attention deficit hyperactivity disorder, IL-6 inhibition, microglial morphology
- MeSH terms
- Animals, Anxiety, Behavior, Animal, Brain, Disease Models, Animal, Female, Male, Pregnancy, Prenatal Exposure Delayed Effects, Stress, Psychological, Interleukin-6, Cytokines, Microglia, GABA Agents, Mice, GABAergic Neurons
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