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Maternal immune activation and abnormal brain development across CNS disorders

Nature Reviews Neurology volume 10, pages 643–660 (2014)Cite this article

Subjects

Key Points

  • The developing brain is particularly sensitive to environmental signals that influence genetically determined developmental processes

  • Infection-induced maternal immune activation (mIA) during pregnancy can have a profound impact on developing neural circuits

  • Strong epidemiological associations exist between exposure to various infections during pregnancy and greater risk of schizophrenia, autism or epilepsy in the progeny

  • Emerging evidence suggests similar links for disorders like cerebral palsy and ageing-associated neurodegenerative diseases, positioning mIA as a factor in the brain's responsiveness to cumulative lifetime exposure to environmental insults

  • Microglia constitute the primary immune mediators of neural functions, and their mIA-induced priming is thought to underlie some of the persistent immunological and/or neurological changes associated with mIA

  • Targeting of immune-related pathways might represent a promising therapeutic strategy for neurodevelopmental, psychiatric and neurological disorders

Abstract

Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies.

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Figure 1: The timeline of development.
Figure 2: Proposed causal chain of events.
Figure 3: Developmental priming pathways.

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Acknowledgements

Support for third-party editorial assistance for this manuscript was provided by Roche. The authors would like to thank Drs Anirvan Ghosh, Omar Khwaja, Christoph Meier, Joseph Wettstein and Urs Meyer for inspiring discussions as well as the late Dr Paul H. Patterson whose work has been a starting point and continuous inspiration for the current Review. We also thank Ruth Habermacher Britschgi for her support in conceptualizing Figure 2. J.A.H. receives funding from the Autism Speaks Autism Treatment Network and the National Institutes of Mental Health, USA.

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Authors and Affiliations

  1. Roche Pharma Research and Early Development, Roche Innovation Centre Basel, Grenzacherstrasse 124, Basel, 4070, Switzerland

    Irene Knuesel, Markus Britschgi, Scott A. Schobel & Eric P. Prinssen

  2. Department of Biomedicine, Brain Ischemia & Regeneration Group, University Hospital, Hebelstrasse 20, Basel, 4031, Switzerland

    Laurie Chicha

  3. Department of Internal Medicine, Emergency Unit, University Hospital, Petersgraben 2, Basel, 4031, Switzerland

    Michael Bodmer

  4. The Nisonger Centre, Ohio State University, 1581 Dodd Drive, Columbus, 43210, OH, USA

    Jessica A. Hellings

  5. Pegasus Research, Burggartenstrasse 32, 4103, Bottmingen, Switzerland

    Stephen Toovey

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Contributions

I.K. and L.C. (equal contribution), together with M. Britschgi, S.A.S. and E.P.P., did the primary searches of the literature and wrote the article. M. Bodmer, J.A.H. and S.T. also contributed to researching data and assisted with writing the article. All authors made substantial contributions to the discussion of content, and helped to revise and/or edit the manuscript before submission.

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Correspondence to Eric P. Prinssen.

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Competing interests

I.K., M. Britschgi, S.A.S. and E.P.P are full-time employees at Roche. J.A.H. is an investigator for studies funded by the Autism Speaks Autism Treatment Network, Forest Laboratories, Shire, Sunovion, and the National Institues of Mental Health, USA, and has been an advisor to Abbott Laboratories and a consultant to Ferring Pharmaceuticals. S.T. is a consultant paid by Roche. The other authors declare no competing interests.

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Knuesel, I., Chicha, L., Britschgi, M. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol 10, 643–660 (2014). https://doi.org/10.1038/nrneurol.2014.187

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