Behavioral analyses of transgenic mice harboring bipolar disorder candidate genes, IMPA1 and IMPA2.

The inositol depletion hypothesis proposes the inhibition of IMPase (myo-inositol monophosphatase) by lithium, a mood stabilizer, as a mechanism of lithium's efficacy. This hypothesis predicts that the upregulation of this biochemical pathway may underlie the pathophysiology of bipolar disorder. In favor of this idea, IMPA2 encoding IMPase is a candidate susceptibility gene for bipolar disorder and that the risk-conferring single nucleotide polymorphisms enhance the promoter activity of IMPA2. However, it is yet unknown whether such upregulation has a biological role in bipolar disorder. To address this issue, we generated transgenic mice for the two IMPase genes (IMPA1 and IMPA2). The expression levels of the transgene were robust in IMPA2 Tg lines, but moderate in IMPA1 Tg lines, when compared to those of endogenous proteins. The transgenic mice behaved normally under drug-naïve conditions, and did not exhibit signs for manic change when an antidepressant amitriptyline was administrated. Interestingly, the male transgenic mice for IMPA2 exhibited a lithium-resistant phenotype in the forced swim test. The current study, as a whole, did not support a substantial role of the upregulation of IMPase in bipolar disorder, although the lithium-insensitivity trait seen in IMPA2 transgenic mice might represent some aspect relevant to the inositol depletion hypothesis.