Cortical gene expression in lithium-treated healthy non-human primate models as windows to mood-stabilizing properties of lithium in bipolar affective disorder

Prabhakara V Choudary; Margherita Molnar; Jun Z Li; Simon J Evans; Hiroaki Tomita; Fan Meng; Marquis P Vawter; Richard M Myers; William E Bunney Jr; Huda Akil; Stanley J Watson; Edward G Jones
International Meeting of the Microarray Gene Expression Data Society. 2005.


Lithium's remarkable mood stabilizing properties have made it a leading drug for decades to treat bipolar affective disorder (manic-depressive illness). However, its efficacy record is based exclusively on alleviation of symptoms rather than correction of biological aberration, i.e., the cause of the disorder. And, studying differential expression using the traditional gene-by-gene approach has led to the identification of a few individual candidate genes in neurons or brain slices, cultured in the presence of lithium. However, to define a more comprehensive biological context of drug-response, one needs to simultaneously analyze several gene products that collectively contribute to the overall pathology via coordinated networks and pathways. To accomplish it without any disease confounds, we investigated gene expression changes in a healthy non-human primate model. We chronically treated rhesus macaque monkeys with lithium, and interrogated total RNA samples purified from frontal cortical regions of the brains with Affymetrix GeneChips (HG_U133 plus 2.0). Analysis of the data using RMA validated some of the candidate genes that have been previously implicated and some identified in our human postmortem studies on bipolar disorder. Our results prove the concept by providing clues to biological processes rather than symptoms that could help in rational design of novel mood stabilizers with improved target-selectivity and efficacy.