Identification and characterization of differentially expressed genes following chronic lithium treatment in rat brain

grantor: University of TorontoThe precise mechanisms underlying the therapeutic actions of lithium in bipolar disorder remain unclear, however, substantial evidence suggests alterations in gene expression may be critical to its long-term mood stabilization. The primary objectives of this study were to screen and identify genes, whose expression is altered in rat frontal cortex following chronic lithium treatment, by mRNA differential display. The pharmacospecificity of lithium's effects on gene expression was subsequently evaluated in comparison to those of anticonvulsant mood stabilizers, valproate and carbamazepine, and non-mood stabilizing psychotropic drugs, haloperidol and imipramine. Analyses by mRNA differential display and northern blotting identified two lithium regulated genes (LRG), LRG1 and LRG2. In addition, a third LRG (LRG3) was serendipitously identified by rapid amplification of cDNA ends. Molecular cloning and DNA sequence analyses of LRG1, LRG2 and LRG3 revealed their identities as aldolase A, diphosphoinositol polyphosphate phosphohydrolase 2 (DIPP2) and CD151, respectively. The mRNA levels of aldolase A (and C isozyme) were significantly reduced by chronic (5 weeks) lithium or carbamazepine treatment. The DIPP2 mRNA levels were increased only by lithium, whereas CD151 mRNA levels were reduced by chronic lithium, valproate or carbamazepine treatment. No significant effect on the mRNA levels of any of these genes was evident following either short-term (1-week) lithium treatment or chronic administration of haloperidol and imipramine, demonstrating time dependence and pharmacological specificity of the lithium's effects. Chronic lithium treatment also reduced the cytosolic, but not particulate, protein levels of aldolase in rat frontal cortex. Although the pharmacotherapeutic relevance of the effects of lithium on the expression of these three genes remains to be further investigated, the observations of a potential role of these gene products in the inositol phosphoinositide metabolism and signaling suggest that lithium may act, at the level of gene expression, on different components of the phosphoinositide signaling cascades, thereby producing its therapeutic efficacy. This suggestion is consistent with the current notion that abnormalities in intracellular signaling, including phosphoinositide signaling, may contribute, at least in part, to the pathophysiology of bipolar disorder.Ph.D