Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder

Reduced inositol monophosphatase (IMPase) activity and elevated basal intra cellular calcium levels ([Ca2+](B)) have been reported in, B lymphoblast ce ll lines (BLCLs) from bipolar I affective disorder (BD-I), patients, which may reflect cellular endophenotypes of this disorder. As the PI cycle coupl es to intracellular Ca2+ mobilization, these two putative endophenotypes ma y be related. Using an RT-PCR assay, mRNA levels were estimated for IMPA1 a nd 2 genes encoding human, IMPase 1 and 2, respectively, in BLCLs phenotype d on [Ca2+](B), from patients with a DSM-IV diagnosis of BD-I (n = 12 per p henotype) and from age- and sex-matched healthy subjects, (n = 12). IMPA2 m RNA levels were significantly lower in BLCLs from male BD-I patients with h igh [Ca2+](B) (n = 6) compared with healthy male subjects (n = 5) (-52%, P = 0.013), male BN patients. with normal BLCL [Ca2+](B) (n = 8) (-42%, P = 0 .003) and female BD-I patients with high [Ca2+](B), (n = 6)(-59%, P = 0.000 4). A significant! negative correlation was observed between IMPA2 mRNA lev els and [Ca2+](B) in BLCLs from male (P = 0.046), but not female BD-I patie nts. Sex-dependent differences were also evident in postmortem temporal cor tex IMPA2 mRNA levels which,, in contrast to BLCLs, were significantly high er in male BD-I subjects compared with, male controls (P = 0.025, n = 4/gro up). Collectively, these observations suggest a potential sex-dependent lin k between: abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD.