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Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism

Abstract

The broad impairments in cognitive and neurologic functioning found in Autism Spectrum Disorder (ASD) patients are thought to originate during early prenatal developmental stages. Indeed, postmortem and imaging studies in ASD patients detected white-matter abnormalities, as well as prefrontal and temporal cortex deficits, evident from early childhood. Here, we used Maternal Immune Activation (MIA), a mouse model for ASD, in which the offsprings exhibit Autistic-like behaviors as well as cortical abnormalities. However, the dynamics that influence the number and the identity of newly born cortical neurons following maternal inflammation remains unknown. Our study shows early changes in the duration of the S-phase of PAX6+ progenitors, leading to an increased proportion of neurogenic divisions and a reciprocal decrease in the proliferative divisions. In two different time points of maternal inflammation, MIA resulted in an overproduction of CTIP2+ cortical neurons, which remained overrepresented at the end of gestation and in postnatal mice. Interestingly, MIA-resistant IL6-KO mice did not exhibit these changes. Lastly, we propose that elevated levels of the transcription factor PAX6 following MIA supports the overproduction of CTIP2+ neurons. Taken together, our data reveals a possible link between maternal immune activation and the excess of cortical neurons found in the cortex of ASD patients.

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Acknowledgements

We are grateful for the help of Ofira Higfa, Yehuda Melamed, Osnat Amram, Oz Yirmiyahu, Michael Tsoory, and Tamar Sapir from the Weizmann Institute of Science. OR is the incumbent of the Bernstein-Mason Chair of Neurochemistry and the Head of M. Judith Ruth Institute for Preclinical Brain Research. The research has been supported by the Israel Science Foundation (Grant No. 347/15), the Legacy Heritage Biomedical Program of the Israel Science Foundation (Grant No. 2041/16), Israel Science Foundation (ISF)—National Natural Science Foundation of China (NSFC) (grant No. 2449/16), grant No. 2397/18 from the Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation, by the European Cooperation on Science and Technology (COST Action CA16118), Weizmann-FAPESP supported by a research grant from Sergio and Sonia Lozinsky, Nella and Leon Benoziyo Center for Neurological Diseases, Jeanne and Joseph Nissim Foundation for Life Sciences Research, Wohl Biology Endowment Fund, Lulu P. and David J. Levidow, Fund for Alzheimers Diseases and Neuroscience Research, the Helen and Martin Kimmel Stem Cell Research Institute, the Kekst Family Institute for Medical Genetics, the David and Fela Shapell Family Center for Genetic Disorders Research.

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Correspondence to Orly Reiner.

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Ben-Reuven, L., Reiner, O. Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism. Mol Psychiatry 26, 1535–1550 (2021). https://doi.org/10.1038/s41380-019-0594-y

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