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

Tai-Na Wu,Chih-Ken Chen,Chun-Ying Chen,Hsiao-Ju Sun,Lawrence Shih-Hsin Wu,Bo-Jian Wu,Chau-Shoun Lee,Andrew Tai-Ann Cheng,Chieh-Hsing Chang

doi:10.1038/s41598-019-46655-1

Abstract

Potassium channel tetramerization domain containing 12 (KCTD12), the auxiliary GABAB 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.

Highlights

For bipolar patients, lithium is the first-line choice for maintenance treatment since it can reduce the risk of relapse and suicide[1,2,3]
T carriers secreted higher amounts of GABA than non-T carriers among healthy controls we found no significant difference between T and non-T carriers among bipolar I (BPI) patients (Supplementary Fig. S1c and Table 1)
We found that BPI patients expressed a higher percentage of KCTD12 expression in macrophage cells than healthy controls and that rs17026688 T carriers secreted lower amounts of Glutamate decarboxylase–like protein 1 (GADL1) and taurine than non-T carriers among Han Chinese BPI patients

Summary

Introduction

Lithium is the first-line choice for maintenance treatment since it can reduce the risk of relapse and suicide[1,2,3]. Chronic administration of lithium is found to decrease the level of taurine in the rat brain[7,8], and the enzyme activity of GADL1 increases significantly in the presence of lithium[9]. The single-nucleotide polymorphism (SNP) rs17026688 in GADL1 has been found to be associated with lithium response in bipolar I (BPI) patients of Han Chinese descent. The use of lithium as a mood stabilizer is found to increase the level of GABA in both plasma and cerebrospinal fluid[21,25,26]. We addressed how lithium and GADL1 influenced the activity of GSK-3, which regulated the expression of KCTD12 using the GADL1 stable overexpression neuroblastoma cell line

Methods

Results

Conclusion