Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory
Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory
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DOI：
10.1073/pnas.95.25.15020
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发表时间：
1998-12-08
影响因子：
11.1
通讯作者：
Kandel, E
中科院分区：
文献类型：
--
作者：
Barad, M;Bourtchouladze, R;Kandel, E
为了改善行为记忆，我们设计了一种策略来放大cAMP通路的信噪比，cAMP通路在海马突触可塑性和行为记忆中起着核心作用。多个高频电刺激序列诱导持久的长时程增强，这是海马体中突触强化的一种形式，其在幅度和持久性上都大于由单个强直序列产生的短暂的长时程增强。使用药理学抑制剂和遗传操作的研究表明，这种反应差异取决于cAMP依赖性蛋白激酶A的活性。遗传学研究还表明，蛋白激酶A及其靶转录因子之一，cAMP反应元件结合蛋白，在体内记忆中是重要的。这些发现表明，通过cAMP途径的信号放大可能会降低产生持久的长时程增强的阈值，并增加行为记忆。因此，我们研究了部分抑制海马cAMP磷酸二酯酶对小鼠的生化、生理和行为的影响。IV型特异性磷酸二酯酶抑制剂，咯利普兰，这对基础cAMP浓度没有显着影响的浓度，增加了海马切片的cAMP反应，刺激与毛喉素和诱导持续长时程增强后，在CA 1一个单一的强直列车。在年轻和老年小鼠中，训练前的咯利普兰治疗增加了长期而不是短期的冻结保留上下文，这是一种依赖于记忆的任务。
In an attempt to improve behavioral memory, we devised a strategy to amplify the signal-to-noise ratio of the cAMP pathway, which plays a central role in hippocampal synaptic plasticity and behavioral memory. Multiple high-frequency trains of electrical stimulation induce long-lasting long-term potentiation, a form of synaptic strengthening in hippocampus that is greater in both magnitude and persistence than the short-lasting long-term potentiation generated by a single tetanic train. Studies using pharmacological inhibitors and genetic manipulations have shown that this difference in response depends on the activity of cAMP-dependent protein kinase A. Genetic studies have also indicated that protein kinase A and one of its target transcription factors, cAMP response element binding protein, are important in memory in vivo. These findings suggested that amplification of signals through the cAMP pathway might lower the threshold for generating long-lasting long-term potentiation and increase behavioral memory. We therefore examined the biochemical, physiological, and behavioral effects in mice of partial inhibition of a hippocampal cAMP phosphodiesterase. Concentrations of a type IV-specific phosphodiesterase inhibitor, rolipram, which had no significant effect on basal cAMP concentration, increased the cAMP response of hippocampal slices to stimulation with forskolin and induced persistent long-term potentiation in CA1 after a single tetanic train. In both young and aged mice, rolipram treatment before training increased long- but not short-term retention in freezing to context, a hippocampus-dependent memory task.