Lithium inhibits neurite growth and tau protein kinase I/glycogen synthasekinase-3 beta-dependent phosphorylation of juvenile tau in cultured hippocampal neurons

Tau protein kinase I (TPKI)/glycogen synthase kinase (GSK)-3 beta is abunda nt in the developing rat brain. The highly phosphorylated juvenile form of tau is present during the same developmental period. To study the role of T PKI/GSK-3b in neuronal growth, we examined the effects of lithium, a direct inhibitor of TPKI/GSK-3 beta, using primary cultures of rat hippocampal ne urons. Immunohistochemical staining of the neurons indicates that in the pr esence of lithium (2-10 mM), neurite growth becomes inhibited in a dose-dep endent manner. Western blot analyses of the cell extracts revealed that the presence of lithium in the culture medium increased the amount of dephosph orylated tau while decreasing phosphorylation at Ser(199) and Ser(396), bot h of which are TPKI/GSK-3b phosphorylation sites on tau. The inhibition by lithium is reversible. Although the amount of TPKI/GSK-3b remained constant , the amount of tau decreased in a dose-dependent manner in the presence of lithium. TPKI/GSK-3b was distributed in the somata and proximal neurites o f the cultured hippocampal neurons. These results therefore suggest that TP KI/GSK-3b plays an important role in the axonal growth of neurons during sy napse formation in the developing brain.