A Role for Calcineurin Dysfunction in Schizophrenia?

Abstract

Schizophrenia, a form of mental illness that affects about 1% of the population, is believed to depend on a complex and incompletely understood interplay of genetic and environmental factors. Two related articles provide evidence suggesting that alterations in signaling from the serine-threonine phosphatase calcineurin may contribute to the pathogenesis of this severe and disabling disease. Miyakawa et al. subjected a strain of mutant mice that lacked forebrain calcineurin to a battery of tests and observed a spectrum of behavioral abnormalities reminiscent of those found in individuals with schizophrenia. The authors, who had previously noted deficits in working memory in these mice, observed decreased social interaction, impaired attention, and impaired nesting behavior. The mice also displayed increased hyperactivity, which is characteristic of other animal models of schizophrenia, and enhanced susceptibility to N-methyl-D-aspartate receptor blockade. In an accompanying article, Gerber et al. demonstrated that the PPP3CC gene, which encodes the calcineurin γ catalytic subunit, mapped to a chromosomal locus previously associated with susceptibility to schizophrenia and displayed a polymorphism that resulted in a nonconservative change in amino acid sequence. Genetic analysis of families affected with schizophrenia suggested that variations in PPP3CC could increase susceptibility to the disease. The authors discuss possible mechanisms whereby abnormalities in calcineurin signaling could predispose to the pathogenesis of schizophrenia.T. Miyakawa, L. M. Leiter, D. J. Gerber, R. R. Gainetdinov, T. D. Sotnikova, H. Zeng, M. G. Caron, S. Tonegawa, Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc. Natl. Acad. Sci. U.S.A. 100, 8987-8992 (2003). [Abstract] [Full Text]D. J. Gerber, D. Hall, T. Miyakawa, S. Demars, J. A. Gogos, M. Karayiorgou, S. Tonegawa, Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc. Natl. Acad. Sci. U.S.A. 100, 8993-8998 (2003). [Abstract] [Full Text]