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Transplantation of mesenchymal stem cells causes long-term alleviation of schizophrenia-like behaviour coupled with increased neurogenesis

Molecular Psychiatry volume 26, pages 4448–4463 (2021)Cite this article

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Abstract

Schizophrenia is a neurodevelopmental disease with a mixed genetic and environmental aetiology. Impaired adult hippocampal neurogenesis was suggested both as a pathophysiological mechanism and as a target for therapy. In the present study, we utilized intracerebroventricular transplantation of bone marrow-derived mesenchymal stem cells (MSC) as a means to enhance hippocampal neurogenesis in the ketamine-induced neurodevelopmental murine model for schizophrenia. Syngeneic MSC have successfully engrafted and survived for up to 3 months following transplantation. Improvement in social novelty preference and prepulse inhibition was noted after transplantation. In parallel to behavioural improvement, increased hippocampal neurogenesis as reflected in the numbers of doublecortin expressing neurons in the dentate gyrus and gene expression was noted both 2 weeks following transplantation as well as 3 months later compared with nontreated animals. An independent aging effect was observed for both behaviour and neurogenesis, which was attenuated by MSC treatment. As opposed to MSC treatment, short-term treatment with clozapine was efficient only during treatment and diminished 3 months later. Interestingly, while shortly after transplantation (2 weeks) behavioural improvement was correlated mainly to FGF2 gene expression, 3 months later it was mainly correlated to the expression of the notch ligand DLL1. This suggests that long-term effect during ageing may depend on neural stem cell self-renewal. We conclude that a single intracerebroventricular injection of bone marrow-derived MSC can suffice for long-term reversal of changes in adult hippocampal neurogenesis and improve schizophrenia-like behavioural phenotype inflicted by developmental exposure to ketamine in mice.

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Fig. 1: Early postnatal ketamine exposure inflicts long-term changes in behaviour and gene expression that are reversed by MSC transplantation.
Fig. 2: Short- and long-term effects of MSC administration on schizophrenia-like behaviour and hippocampal neurogenesis.
Fig. 3: Short- and long-term effects of MSC administration on neurogenesis-related gene expression.
Fig. 4: Short- and long-term effects of MSC administration on hippocampal cytokine levels and cell engraftment.

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Authors and Affiliations

  1. Department of Molecular Biology, Ariel University, Ariel, Israel

    Nikolai Gobshtis, Matanel Tfilin & Gadi Turgeman

  2. The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    Nikolai Gobshtis & Vadim E. Fraifeld

  3. Department of Pre-Medical Studies, Ariel University, Ariel, Israel

    Gadi Turgeman

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Gobshtis, N., Tfilin, M., Fraifeld, V.E. et al. Transplantation of mesenchymal stem cells causes long-term alleviation of schizophrenia-like behaviour coupled with increased neurogenesis. Mol Psychiatry 26, 4448–4463 (2021). https://doi.org/10.1038/s41380-019-0623-x

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