Lee Eminy H Y, Hsu W L, Ma Y L, Lee P J, Chao C C
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Eur J Neurosci. 2003 Nov;18(10):2842-52. doi: 10.1111/j.1460-9568.2003.03032.x.
We have previously demonstrated that the serum and glucocorticoid-inducible kinase (sgk) gene plays a causal role in facilitating memory performance in rats. Environment enrichment is known to facilitate spatial learning. We therefore examined the effect of enrichment on sgk expression. We also examined the role of sgk in spatial and nonspatial learning and the regulation of sgk expression by activation of different glutamate receptors. Both real-time polymerase chain reaction and Western blot analyses revealed that enrichment training preferentially increased sgk mRNA and protein levels in the hippocampus. Transfection of sgk mutant DNA to the hippocampal CA1 area markedly impaired spatial learning, fear-conditioning learning and novel object-recognition learning in rats, but enrichment training effectively reversed these learning deficits. Meanwhile, S422A mutant DNA transfection prevented enrichment-induced spatial learning facilitation. In studying glutamate receptor regulation of sgk expression, we found that blockade of N-methyl-d-aspartate (NMDA) receptors in general, and the NR2B subunit in particular both effectively blocked enrichment-induced spatial learning facilitation, but they did not block enrichment-induced sgk expression. Upon various glutamate agonist infusions, only alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) increased sgk mRNA levels significantly in the hippocampus. Furthermore, blockade of AMPA receptors effectively blocked both enrichment-induced spatial learning facilitation and sgk expression. These results indicate that there is a dissociation between NMDA receptor activation and sgk expression. Enrichment enhanced spatial learning through both NMDA and AMPA receptor activation, whereas enrichment-induced sgk expression is specifically mediated through AMPA receptors. These results suggest that sgk could serve as a novel molecular mechanism, in addition to the NMDA receptor NR2B, underlying enrichment-induced learning facilitation.
我们之前已经证明，血清和糖皮质激素诱导激酶（sgk）基因在促进大鼠记忆表现中起因果作用。已知环境富集可促进空间学习。因此，我们研究了富集对sgk表达的影响。我们还研究了sgk在空间和非空间学习中的作用以及不同谷氨酸受体激活对sgk表达的调节。实时聚合酶链反应和蛋白质免疫印迹分析均显示，富集训练优先增加海马体中sgk的mRNA和蛋白质水平。将sgk突变DNA转染至海马CA1区显著损害大鼠的空间学习、恐惧条件学习和新物体识别学习，但富集训练有效逆转了这些学习缺陷。同时，S422A突变DNA转染阻止了富集诱导的空间学习促进作用。在研究谷氨酸受体对sgk表达的调节时，我们发现一般阻断N-甲基-D-天冬氨酸（NMDA）受体，特别是NR2B亚基，均有效阻断了富集诱导的空间学习促进作用，但它们并未阻断富集诱导的sgk表达。在注入各种谷氨酸激动剂后，只有α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）显著增加了海马体中sgk的mRNA水平。此外，阻断AMPA受体有效阻断了富集诱导的空间学习促进作用和sgk表达。这些结果表明NMDA受体激活与sgk表达之间存在分离。富集通过NMDA和AMPA受体激活增强空间学习，而富集诱导的sgk表达则通过AMPA受体特异性介导。这些结果表明，除了NMDA受体NR2B外，sgk可能作为一种新的分子机制，是富集诱导学习促进作用的基础。
