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Serum‐ and glucocorticoid‐inducible kinase1 enhances contextual fear memory formation through down‐regulation of the expression of Hes5
Author(s) -
Lee Ching T.,
Ma Yun L.,
Lee Eminy H. Y.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04284.x
Subject(s) - sgk1 , kinase , transfection , microbiology and biotechnology , biology , phosphorylation , glucocorticoid , extracellular , downregulation and upregulation , chemistry , endocrinology , medicine , gene , biochemistry
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 , sgk S78A, to hippocampal neurons impaired, whereas transfection of the constitutively active sgk , sgk S78D, enhanced fear retention. Microarray analysis identified 14 genes that showed more than threefold alteration in their gene expression in sgk S78A‐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 sgk S78A‐transfected animals. Further analyses revealed that Hes5 level is markedly decreased after training in control animals, but sgk S78A 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 sgk S78A. These results together suggest that Hes5 negatively regulates contextual fear memory formation and SGK activation down‐regulates Hes5 expression to enhance fear retention.