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.