Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity
Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity
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DOI：
10.1101/lm.661908
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发表时间：
2008-01-01
影响因子：
2
通讯作者：
Klann, Eric
中科院分区：
文献类型：
--
作者：
Antion, Marcia D.;Merhav, Maayan;Klann, Eric
蛋白质合成是表达持久记忆和持久突触可塑性所必需的。在细胞增殖和生长过程中，S6蛋白(S6Ks)被激活，协调从头蛋白的合成。我们推测，S6Ks介导的蛋白质合成对学习、记忆和突触可塑性的表现至关重要。我们已经用S6K1或S6K2基因缺陷的转基因小鼠验证了这一假设。我们发现，S6K1基因缺陷小鼠在训练后一小时内表现出早发性情景恐惧记忆缺陷，条件性味觉厌恶(CTA)缺陷，Morris水迷宫获取受损，以及低活动探索行为。相比之下，S6K2基因缺陷的小鼠在训练后7天表现出上下文恐惧记忆减少，CTA潜在抑制减少，在Morris水迷宫中正常的空间学习。令人惊讶的是，S6K1和S6K2缺陷小鼠都没有表现出蛋白质合成依赖的晚期长时程增强(L-LTP)的变化。然而，去除S6K1，而不是S6K2，会影响早期LTP的表达。此外，我们观察到S6K1缺陷小鼠的Akt基础磷酸化水平升高，在L-LTP诱导后进一步升高。综上所述，我们的发现表明，S6K1的移除导致了一系列不同的行为和突触可塑性表型，而S6K2的移除并不反映这些表型。我们的观察表明，这两个基因本身都不是L-LTP所必需的，而可能是认知加工所需的其他类型的突触可塑性所必需的。
Protein synthesis is required for the expression of enduring memories and long-lasting synaptic plasticity. During cellular proliferation and growth, S6 kinases (S6Ks) are activated and coordinate the synthesis of de novo proteins. We hypothesized that protein synthesis mediated by S6Ks is critical for the manifestation of learning, memory, and synaptic plasticity. We have tested this hypothesis with genetically engineered mice deficient for either S6K1 or S6K2. We have found that S6K1-deficient mice express an early-onset contextual fear memory deficit within one hour of training, a deficit in conditioned taste aversion (CTA), impaired Morris water maze acquisition, and hypoactive exploratory behavior. In contrast, S6K2-deficient mice exhibit decreased contextual fear memory seven days after training, a reduction in latent inhibition of CTA, and normal spatial learning in the Morris water maze. Surprisingly, neither S6K1-nor S6K2-deficient mice exhibited alterations in protein synthesis-dependent late-phase long-term potentiation (L-LTP). However, removal of S6K1, but not S6K2, compromised early-phase LTP expression. Furthermore, we observed that S6K1-deficient mice have elevated basal levels of Akt phosphorylation, which is further elevated following induction of L-LTP. Taken together, our findings demonstrate that removal of S6K1 leads to a distinct array of behavioral and synaptic plasticity phenotypes that are not mirrored by the removal of S6K2. Our observations suggest that neither gene by itself is required for L-LTP but instead may be required for other types of synaptic plasticity required for cognitive processing.