Differential effects of mood stabilizers on Fos/Jun proteins and AP-1 DNA binding activity in human neuroblastoma SH-SY5Y cells

Abstract

Lithium and sodium valproate (VPA) are effective in the treatment of bipolar disorder (BD) and may function through the regulation of signal transduction pathways and transcription factors such as c-fos and c-Jun, which in turn results to changes in gene expression. The long-term efficacy of lithium and VPA in BD suggests that the regulation of gene expression may be an important target for these drugs. Preliminary evidence suggests that c-fos levels and AP-1 binding may be regulated by lithium and VPA, but the results are inconclusive. In the present study, we report differential effects of the two most commonly prescribed mood stabilizers used to treat BD on Fos/Jun protein levels and their AP-1 binding activity in human neuroblastoma SH-SY5Y cells. At therapeutically relevant concentrations, both drugs acutely (<24 h) induced c-Fos immunoreactivity and AP-1 binding. In contrast to lithium, chronic (1 week) treatment with VPA led to continued induction of c-Fos, in addition to induction of c-Jun immunoreactivity and a 33-35 kDa band previously identified as chronic FRA. AP-1 DNA binding activity was also increased after 1 week VPA treatment. These findings suggest that both these mood stabilizers may have an effect on neuronal gene expression of target genes containing the AP-1 consensus sequence in their promoter regions after acute treatment. The present results confirm and extend previous findings on the regulation of c-fos expression and AP-1 binding after administration of mood stabilizers, and further elucidate the mechanisms through which VPA increases AP-1 DNA binding.