Microarray gene expression profiling of mouse brain mRNA in a model of lithium treatment.

OBJECTIVES

Even after five decades of use, the mood stabilizer lithium continues to be the mainstay of treatment for bipolar disorder in many countries. The mechanism of action for lithium, however, remains unclear.

METHODS

In this study, microarray analysis was used to identify genes and cellular pathways that are altered in the mouse brain after treatment with lithium at human therapeutic concentrations. Mice received daily injections of lithium chloride for 7 consecutive days. Whole-brain total RNA was used as a template for microarray gene expression profiling.

RESULTS

This study has identified 19 transcripts that are differentially expressed by four-fold when compared with control untreated mice. The altered expression of these genes was validated by quantitative PCR analysis with five genes showing significant differential expression. Lithium was found to significantly decrease the expression of metallothionein 3 (MT3), ATPase, Na/K transporting, alpha1 polypeptide (ATP1A1), transcription elongation factor B (SIII)-polypeptide 2 (TCEB2), proteasome subunit beta type 5 (PSMB5), and guanine nucleotide binding protein beta1 (GNB1).

CONCLUSION

These genes are involved in a diverse range of biological functions, including maintaining metal ion homeostasis and chemical/electrical gradients across membranes, regulating RNA polymerase II, protein degradation, and G-protein-coupled signal transduction. These results indicate that lithium can regulate a large number of different cellular pathways in the brain. Understanding the molecular and cellular mechanisms by which lithium achieves its therapeutic action represents a valuable step in clarifying the pathophysiology of bipolar disorder.