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Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia

Molecular Psychiatry volume 23, pages 943–951 (2018)Cite this article

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Abstract

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia’s neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

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Acknowledgements

We thank Renate Winter, Doris Zschaber and Roselies Pickert for excellent technical assistance. This research was conducted under the EraNet Neuron framework (DBS_F20rat) and supported by the BMBF, Germany (B01EW1103, 01EE1403A), Fundación Mapfre, Comunidad de Madrid and the Ministry of Economy and Competitiveness ISCIII-FIS grants (PI14/00860, CPII/00005) co-financed by ERDF (FEDER) Funds from the European Commission, ‘A way of making Europe’, Spain (PI14/00860, CPII/00005, MV1500002), the CSO-MOH, Israel (3-8580) and the Canadian Institutes of Health Research, Canada (CIHR, 110068), and co-financed by the DFG, Germany (WI 2140/1-1/2; WI 2140/2-1).

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Author notes

  1. I Weiner and C Winter: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    R Hadar, J Schimke, P Maier, S Ewing, M Voget, F Wieske, T Götz & C Winter

  2. Department of Psychiatry and Psychotherapy, Division of Experimental and Molecular Psychiatry, Charité – Universitätsmedizin Berlin, Berlin, Germany

    R Hadar & C Winter

  3. School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel

    L Bikovski & I Weiner

  4. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    L Bikovski & I Weiner

  5. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    M L Soto-Montenegro, M Desco & J Pascau

  6. CIBERSAM, Madrid, Spain

    M L Soto-Montenegro, M Desco & J Pascau

  7. International Graduate Program Medical Neurosciences, Charité – Universitätsmedizin Berlin, Berlin, Germany

    M Voget

  8. Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Madrid, Spain

    M Desco & J Pascau

  9. Behavioural Neurobiology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada

    C Hamani

  10. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    C Hamani

  11. Division of Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada

    C Hamani

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  1. R Hadar
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Correspondence to C Winter.

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Hadar, R., Bikovski, L., Soto-Montenegro, M. et al. Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia. Mol Psychiatry 23, 943–951 (2018). https://doi.org/10.1038/mp.2017.52

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