Inositol-metabolizing enzyme gene-manipulated mice towards molecular dissection of pathophysiology of mental disorders.

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In this study, we successfully developed mice with manipulated genes for IMPase (inositol monophosphatase) : Impa1-Tg, Impa2-Tg, Impa1-ENU and Impa2-KO mice. Among them, transgenic mice with brain-specific IMPA2 overexpression exhibited moderate anxiety phenotype when evaluated in elevated plus maze (EPM) and light and dark (LD) box tests. Our analysis showed that at least one of three Impa1-ENU lines, where a missense mutation is introduced by a mutagen ENU (ethyl-nitroso-urea) at different position in the coding region of Impal gene, completely losses the enzymatic activity given by the Impal protein.Our study also showed that a promoter haplotype of IMPA2 confers a possible risk for bipolar disorder in Japanese population possibly by enhancing transcription. Taken together with phenotype of Impa2-Tg mice, these data strongly suggest the function of IMPA2 in the pathogenesis of mood disorders, in particular, bipolar disorder.Moreover, we first proved that the IMPA2 protein exhibits IMPase activity in vitro. IMPA1 and IMPA2 show clearly different tissue distributions, and have different sensitivities to lithium. To obtain further insight for the IMPA2 gene product, we first revealed the crystal structure of this protein. While the overall structure of the IMPA2 protein is similar to that of IMPA1, which exhibits lithium-inhibitable strong IMPase activity, IMPA2 possesses more widely opened cavity than that of IMPA1. These observations imply a specific function of IMPA2 in the biochemical process(es) in the cell, possibly having specific in vivo substrate(s), which is different from that for IMPA1.