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Impact of early social isolation on social circuits and behavior: relevance to schizophrenia

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Abstract

Social deficits are a core feature of many psychiatric disorders. Importantly, aberrant social experiences during childhood and adolescence profoundly influence maturation of the brain function and induce social impairments in adulthood. Social isolation, especially among youth, has been highlighted as a serious risk to mental health. As a result, understanding the consequences of social isolation on a mechanistic level has become increasingly urgent. Recent rodent studies have revealed that social isolation during development induces widespread changes in adult brain structures, particularly in the prefrontal cortical circuits, and causes altered social behavior. These findings led us to develop two models proposing that social isolation may cause deficits through either concurrent (social deprivation model) or subsequent (developmental mismatch model) to social disruption. Building on these two models, this review examines how these models provide complementary perspectives on the influence of social isolation on the progression of schizophrenia, from the prodromal to the psychotic phase, a condition in which genetic and environmental risk factors are closely linked to social isolation. Advancing our understanding of treatment timing and targets for isolation-induced social deficits through the lenses of these models may help identify the optimal developmental timing for effective interventions and prevention strategies for schizophrenia.

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Fig. 1: mPFC social circuits vulnerable to juvenile social isolation in mice.
Fig. 2: Social circuits beyond the PFC that are impacted by juvenile social isolation in mice.
Fig. 3: Overview of the social deprivation model, developmental mismatch model, and development of schizophrenia.

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Funding

This work was supported by the National Institute of Mental Health: R01MH118297 to Hirofumi Morishita and F31MH127805 to Michael B. Leventhal, National Institute on Drug Abuse: R34DA061263 to Hirofumi Morishita, the Simons Foundation/SFARI (grant no. 610850) to Hirofumi Morishita, and the Heiwa Nakajima Foundation to Ayako Kawatake-Kuno.

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Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ayako Kawatake-Kuno, Michael B. Leventhal & Hirofumi Morishita

  2. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ayako Kawatake-Kuno, Michael B. Leventhal & Hirofumi Morishita

  3. Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ayako Kawatake-Kuno, Michael B. Leventhal & Hirofumi Morishita

  4. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ayako Kawatake-Kuno, Michael B. Leventhal & Hirofumi Morishita

  5. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ayako Kawatake-Kuno, Michael B. Leventhal & Hirofumi Morishita

  6. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

    Hirofumi Morishita

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  1. Ayako Kawatake-Kuno
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  2. Michael B. Leventhal
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Contributions

Ayako Kawatake-Kuno, Michael B. Leventhal, and Hirofumi Morishita conceptualized the research goals and aims of this manuscript. Ayako Kawatake-Kuno and Michael B. Leventhal curated and analyzed references used to inform this manuscript, with help from Hirofumi Morishita acquired funding to write this manuscript. Hirofumi Morishita supervised this project. Visualizations were created by Ayako Kawatake-Kuno and Michael B. Leventhal revised with feedback from Hirofumi Morishita. The original draft of this manuscript was produced by Ayako Kawatake-Kuno and Michael B. Leventhal. The manuscript was reviewed and edited by all authors.

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Correspondence to Hirofumi Morishita.

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Kawatake-Kuno, A., Leventhal, M.B. & Morishita, H. Impact of early social isolation on social circuits and behavior: relevance to schizophrenia. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02156-6

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