Serum- and glucocorticoid-inducible kinase1 enhances contextual fear memory formation through down-regulation of the expression of Hes5.

Mitogen-activated protein kinase/extracellular signal-regulated kinase plays an important role in memory formation and directly phosphorylates serum- and glucocorticoid-inducible kinase1 (SGK1) at Ser78. In this study, we examined the role and mechanism of SGK1 Ser78 activation involved in contextual fear memory formation in rats. Results revealed that SGK1 Ser78 phosphorylation was increased 30 min, 1 h and 3 h after training. Transient transfection of the dominant negative mutant of sgk, sgkS78A, to hippocampal neurons impaired, whereas transfection of the constitutively active sgk, sgkS78D, enhanced fear retention. Microarray analysis identified 14 genes that showed more than threefold alteration in their gene expression in sgkS78A-transfected animals 6 h after training. One of them is Hairy and Enhancer of split 5 (Hes5). The expression level of Hes5 is approximately 4.4-fold higher in sgkS78A-transfected animals. Further analyses revealed that Hes5 level is markedly decreased after training in control animals, but sgkS78A markedly increased Hes5 level after training. RNA interference experiment showed that shHes5 dose-dependently enhanced fear retention, whereas over-expression of Hes5 impaired fear retention. Moreover, shHes5 at a lower concentration completely blocked the memory-impairing effect of sgkS78A. These results together suggest that Hes5 negatively regulates contextual fear memory formation and SGK activation down-regulates Hes5 expression to enhance fear retention.