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Microglia as critical mediators linking perinatal immune stress to mental health trajectories

Neuropsychopharmacology (2025)Cite this article

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Abstract

Neurodevelopmental and neuropsychiatric disorders that emerge in childhood (such as autism) and adolescence (such as depression and schizophrenia) currently lack broadly effective therapies, underlying an urgent need to better understand their etiology. While each disorder has its own set of complex genetic and environmental risk factors, perinatal exposure to intense immune activation and/or stress has been linked to increased disease risk. Microglia, the resident immune cells of the brain, are impacted in each disorder and exquisitely sensitive to early life experience. Here, we review the literature suggesting microglia-specific changes in response to early life immune activation and/or stress with an emphasis on microglial interactions with neural synapses and circuits. We also review the existing literature linking these findings to microglia-specific changes in the brain in autism, depression, and schizophrenia. Our goal is to bridge the gap between developmental insults and the subsequent pathogenesis of these disorders, highlighting key areas for future mechanistic work.

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Fig. 1: Simplified comparison of the effects of pre- and postnatal immune activation and stress on microglial morphology and interactions with neurons.
Fig. 2: Perinatal insults impact microglial biology across development.

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Acknowledgements

This work was supported by NIEHS R00ES033278 to CJS.

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Authors and Affiliations

  1. Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Ravikiran M. Raju

  2. Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA

    Ravikiran M. Raju

  3. Biology of Adversity Project, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ravikiran M. Raju

  4. Department of Psychology and Neuroscience, Boston College, Chestnut Hill, MA, USA

    Caroline J. Smith

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RMR and CJS contributed equally to the conceptualization and writing of this manuscript.

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Raju, R.M., Smith, C.J. Microglia as critical mediators linking perinatal immune stress to mental health trajectories. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02162-8

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