Protein phosphatase 1 is a molecular constraint on learning and memory
Protein phosphatase 1 is a molecular constraint on learning and memory
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DOI：
10.1038/nature00928
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发表时间：
2002-08-29
期刊：
影响因子：
64.8
通讯作者：
Mansuy, IM
中科院分区：
文献类型：
--
作者：
Genoux, D;Haditsch, U;Mansuy, IM
重复学习是形成准确而持久的记忆的先决条件。实践是最有效的，当广泛分布在时间上，而不是当紧密间隔或集中。但是，即使在有效的学习之后，大多数记忆也会随着时间的推移而消失，除非经常使用(1，2)。这些依赖于时间的限制对学习和记忆的分子机制尚不清楚。在这里，我们证明了蛋白磷酸酶1(PP1)通过限制获得和促进记忆衰退来决定学习和记忆的有效性。当PP1在学习过程中受到遗传抑制时，训练片段之间的较短间隔就足以实现最佳性能。学习能力的增强与循环AMP依赖的反应元件结合(CREB)蛋白、钙/钙调蛋白依赖的蛋白激酶II(CaMKII)和AMPA受体的GluR1亚单位的磷酸化增加相关；它还与CREB依赖的基因表达相关，在对照组小鼠中，只有在广泛分布的训练中才会发生这种情况。抑制PP1在学习后诱导时会延长记忆，这表明PP1也会促进遗忘。这一特性可能解释了与衰老相关的认知衰退，因为年老的突变动物保留了记忆。我们的发现强调了PP1的生理重要性，它是学习和记忆的抑制者，也是衰老过程中认知能力下降的潜在中介。
Repetition in learning is a prerequisite for the formation of accurate and long-lasting memory. Practice is most effective when widely distributed over time, rather than when closely spaced or massed. But even after efficient learning, most memories dissipate with time unless frequently used(1,2). The molecular mechanisms of these time-dependent constraints on learning and memory are unknown. Here we show that protein phosphatase 1 (PP1) determines the efficacy of learning and memory by limiting acquisition and favouring memory decline. When PP1 is genetically inhibited during learning, short intervals between training episodes are sufficient for optimal performance. The enhanced learning correlates with increased phosphorylation of cyclic AMP-dependent response element binding (CREB) protein, of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and of the GluR1 subunit of the AMPA receptor; it also correlates with CREB-dependent gene expression that, in control mice, occurs only with widely distributed training. Inhibition of PP1 prolongs memory when induced after learning, suggesting that PP1 also promotes forgetting. This property may account for ageing-related cognitive decay, as old mutant animals had preserved memory. Our findings emphasize the physiological importance of PP1 as a suppressor of learning and memory, and as a potential mediator of cognitive decline during ageing.