Lithium (Li(+)) is a common treatment for
bipolar mood disorder, a major
psychiatric illness with a lifetime prevalence of more than 1%. Risk of
bipolar disorder is heavily influenced by
genetic predisposition, but is a complex genetic trait and, to date, genetic studies have provided little insight into its molecular origins. An alternative approach is to investigate the genetics of Li(+) sensitivity. Using the social amoeba Dictyostelium, we previously identified
prolyl oligopeptidase (PO) as a modulator of Li(+) sensitivity. In a link to the clinic, PO
enzyme activity is altered in
bipolar disorder patients. Further studies demonstrated that PO is a negative regulator of
inositol(1,4,5)trisphosphate (IP(3)) synthesis, a Li(+) sensitive intracellular signal. However, it was unclear how PO could influence either Li(+) sensitivity or risk of
bipolar disorder. Here we show that in both Dictyostelium and cultured human cells PO acts via
Multiple Inositol Polyphosphate Phosphatase (Mipp1) to control gene expression. This reveals a novel, gene regulatory network that modulates
inositol metabolism and Li(+) sensitivity. Among its targets is the
inositol monophosphatase gene IMPA2, which has also been associated with risk of
bipolar disorder in some family studies, and our observations offer a cellular signalling pathway in which PO activity and IMPA2 gene expression converge.