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Potassium channel tetramerization domain containing 12 ( KCTD12 ), the auxiliary GABA B  receptor subunit, is identified as a susceptibility gene for bipolar I (BPI) disorder in the Han Chinese population. Moreover, the single-nucleotide polymorphism (SNP) rs17026688 in glutamate decarboxylase–like protein 1 ( GADL1 ) is shown to be associated with lithium response in Han Chinese BPI patients. In this study, we demonstrated for the first time the relationship among lithium, GADL1, and KCTD12. In circulating CD11b +  macrophage cells, BPI patients showed a significantly higher percentage of KCTD12 expression than healthy controls. Among BPI patients, carriers of the ‘T’ allele (i.e., CT or TT) at site rs17026688 were found to secrete lower amounts of GADL1 but higher amounts of GABA b receptor 2 (GABBR2) in the plasma. In human SH-SY5Y neuroblastoma cells, lithium treatment increased the percentage of KCTD12 expression. Through inhibition of glycogen synthase kinase-3 (GSK-3), lithium induced cyclic AMP-response element binding protein (CREB)–mediated  KCTD12  promoter activation. On the other hand,  GADL1  overexpression enhanced GSK-3 activation and inhibited  KCTD12  expression. We found that lithium induced, whereas GADL1 inhibited,  KCTD12  expression. These findings suggested that  KCTD12  may be an important gene with respect to neuron excitability and lithium response in BPI patients. Therefore, targeting GSK-3 activity and/or  KCTD12  expression may constitute a possible therapeutic strategy for treating patients with BPI disorder.

Lithium and GADL1 regulate glycogen synthase kinase-3 activity to modulate KCTD12 expression