Delineating lithium-responsive gene cascades using a non-human primate model

P.V. Choudary; M. Molnar; J.Z. Li; S.J. Evans; H. Tomita; F. Meng; M.P. Vawter; R.M. Myers; W.E. Bunney; H. Akil; S.J. Watson; E.G. Jones
Society for Neuroscience annual meeting. 2005.


Lithium has long been the drug of choice for treating manic-depressive illness (bipolar affective disorder). Its unique mood stabilization properties have made lithiums cellular effects the subject of extensive investigations. While these studies have led to the identification of some putative lithium-responsive candidate genes, a majority of the explorations have been conducted using neurons or brain slices cultured in the presence of lithium. To delineate the molecular mechanism of action of lithium in a context more closely resembling the clinical setting of treating manic-depression with lithium, we designed a microarray study using healthy rhesus macaque monkey as a non-human primate model. The experimental subjects were chronically treated with lithium, and differential gene expression patterns of their brains were profiled using high-density oligonucleotide arrays. We discuss therapeutic relevance of the results and their overlap or lack thereof with our human postmortem findings. Validated results, by facilitating reconstruction of the genetic networks underlying manic-depression pathophysiology, can potentially help the design of target-selective rational mood stabilizers. We cordially thank X. Fan, P. Nguyen, M. Yusufzai, S. Burke, M. Hoversten, M.F. Lopez, T. Speed, B. Bolstad, J. Brettenbaugh, M. Dai, and Y. Wang for expert technical help and discussions.