The mechanisms underlying lithium's therapeutic efficacy in the chronic 
treatment of bipolar disorder are not clearly understood. Useful insights can be 
obtained by identifying genes that are differentially regulated during chronic 
lithium treatment. Toward this end, we have used microarray technology to 
identify mRNAs that are differentially expressed in a human neuronal cell line 
that has been continuously maintained in therapeutic levels of lithium for 33 
days. Significantly, unlike other transcriptomes where predominantly rodent 
cells were used and a limited number of genes probed, we have used human cells 
probed with more extensive 44,000 gene microarrays. A total of 671 
differentially regulated transcripts, after correcting for false discovery 
rates, were identified, of which 347 and 324, respectively, were found to be up- 
and downregulated. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, was the most 
upregulated while tribbles homolog 3 (TRB3), a pro-apoptotic protein, was the 
most downregulated, implying a beneficial effect of lithium on neuronal cells. 
Several of the most highly regulated genes are novel, uncharacterized and encode 
proteins of unknown function. Differentially expressed genes associated with 
phosphoinositide metabolism include those encoding phosphatidyl inositol 
4-phosphate 5-kinase type II alpha (PIP5K2A), WD repeat domain, phosphoinositide 
interacting 1 protein (WIPI49), tribbles homolog 3 (TRB3) and sorting nexin 14 
(SNX14). A protein interactome using some of the saliently regulated genes 
identified protein kinase C (PKC) as a major target for lithium action while a 
global analysis of all 671 differentially expressed genes identified the 
mitogen-activated protein kinase pathway as the most regulated. The list of 
highly regulated genes, besides encoding putative targets for antimanic agents, 
should prove useful in defining novel pathways, or to better understand the 
mechanisms, underlying the mood stabilization process.