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Dysregulation of kisspeptin and neurogenesis at adolescence link inborn immune deficits to the late onset of abnormal sensorimotor gating in congenital psychological disorders

Molecular Psychiatry volume 15, pages 415–425 (2010)Cite this article

Abstract

Neuropsychological syndromes including schizophrenia often do not manifest until late adolescence or early adulthood. Studies attributing a role in brain maintenance to the immune system led us to propose that malfunction of immune-dependent regulation of brain functions at adolescence underlies the late onset of such diseases/syndromes. One such function is sensorimotor gating, the ability to segregate a continuous stream of sensory and cognitive information, and to selectively allocate attention to a significant event by silencing the background (measured by prepulse inhibition; PPI). This activity is impaired in schizophrenia, as well as in several other neuropsychological diseases. Using a model of prenatal immune activation (maternal polyriboinosinic–polyribocytidylic acid (poly I:C) injection), often used as a model for schizophrenia, and in which abnormal PPI has a delayed appearance, we demonstrated a form of immune deficit in the adult offspring. Similar abnormal PPI with a delayed appearance was found in congenitally immune-deficient mice (severe combined immune deficient, SCID), and could be reversed by immune reconstitution. This functional deficit correlated with impairment of both hippocampal neurogenesis and expression of the gene encoding kisspeptin (Kiss1) that manifested at adulthood. Moreover, exogenous administration of a kisspeptin-derived peptide partially reversed the gating deficits in the SCID mice. Our results suggest that a form of congenital immune deficiency may be a key factor that determines manifestation of developmental neuropsychological disorders with onset only at early adulthood.

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Acknowledgements

This study was supported by a grant from the National Alliance for Research on Schizophrenia and Depression (NARSAD), and by the ERC award given to MS. MS is the incumbent of the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. We thank S Schwarzbaum for editing the paper, and S Ovadia and M Azulay for animal handling.

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  1. G M Lewitus

    Present address: 3Current address: Department of Neurology and Department of Neurosurgery, Centre for Research in Neuroscience, The McGill University Health Center, Montreal, QC, Canada.,

  2. M Cardon and N Ron-Harel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel

    M Cardon, N Ron-Harel, G M Lewitus & M Schwartz

  2. Ministry of Health Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

    H Cohen

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Correspondence to G M Lewitus or M Schwartz.

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Cardon, M., Ron-Harel, N., Cohen, H. et al. Dysregulation of kisspeptin and neurogenesis at adolescence link inborn immune deficits to the late onset of abnormal sensorimotor gating in congenital psychological disorders. Mol Psychiatry 15, 415–425 (2010). https://doi.org/10.1038/mp.2009.66

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